KAT5

Summary

KAT5 (lysine acetyltransferase 5, HGNC:5275) is a protein-coding gene on chromosome 11q13.1, encoding Histone acetyltransferase KAT5 (Q92993). Catalytic subunit of the NuA4 histone acetyltransferase complex, a multiprotein complex involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H2A and H4. It is a selective cancer dependency (DepMap: 69.7% of cell lines).

The protein encoded by this gene belongs to the MYST family of histone acetyl transferases (HATs) and was originally isolated as an HIV-1 TAT-interactive protein. HATs play important roles in regulating chromatin remodeling, transcription and other nuclear processes by acetylating histone and nonhistone proteins. This protein is a histone acetylase that has a role in DNA repair and apoptosis and is thought to play an important role in signal transduction. Alternative splicing of this gene results in multiple transcript variants.

Source: NCBI Gene 10524 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with dysmorphic facies, sleep disturbance, and brain abnormalities (Strong, GenCC)
• GWAS associations: 25
• Clinical variants (ClinVar): 155 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 40
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 69.7% of screened cell lines
• Transcription factor: yes — 63 downstream targets (CollecTRI)
• MANE Select transcript: NM_182710

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5275
Approved symbol	KAT5
Name	lysine acetyltransferase 5
Location	11q13.1
Locus type	gene with protein product
Status	Approved
Aliases	TIP60, PLIP, cPLA2, HTATIP1, ESA1
Ensembl gene	ENSG00000172977
Ensembl biotype	protein_coding
OMIM	601409
Entrez	10524

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 13 protein_coding, 4 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000341318, ENST00000352980, ENST00000377046, ENST00000525204, ENST00000525600, ENST00000527544, ENST00000528198, ENST00000530446, ENST00000530605, ENST00000531880, ENST00000532042, ENST00000533441, ENST00000533596, ENST00000534104, ENST00000534293, ENST00000534650, ENST00000534681, ENST00000948346, ENST00000948347

RefSeq mRNA: 4 — MANE Select: NM_182710 NM_001206833, NM_006388, NM_182709, NM_182710

CCDS: CCDS31610, CCDS55771, CCDS8109, CCDS8110

Canonical transcript exons

ENST00000341318 — 13 exons

Exon	Start	End
ENSE00001191008	65718590	65718749
ENSE00001191015	65716889	65716982
ENSE00001191023	65716667	65716807
ENSE00001414981	65712252	65712445
ENSE00002180352	65719047	65719604
ENSE00003462372	65718873	65718954
ENSE00003464410	65714821	65714910
ENSE00003483314	65712922	65713058
ENSE00003492183	65712766	65712834
ENSE00003592795	65713348	65713503
ENSE00003595616	65713593	65713667
ENSE00003645581	65713774	65713848
ENSE00003687383	65714495	65714743

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 95.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.8711 / max 119.9135, expressed in 1787 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
115205	6.0851	1707
115204	3.5409	1568
115206	0.2450	85

Top tissues by expression

293 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	95.89	gold quality
right lobe of thyroid gland	UBERON:0001119	94.99	gold quality
body of uterus	UBERON:0009853	94.98	gold quality
mucosa of stomach	UBERON:0001199	94.83	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.74	gold quality
cerebellar hemisphere	UBERON:0002245	94.54	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.52	gold quality
left lobe of thyroid gland	UBERON:0001120	94.47	gold quality
cerebellar cortex	UBERON:0002129	94.46	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.45	gold quality
left uterine tube	UBERON:0001303	94.36	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.34	gold quality
popliteal artery	UBERON:0002250	94.32	gold quality
tibial artery	UBERON:0007610	94.32	gold quality
lower esophagus	UBERON:0013473	94.32	gold quality
ectocervix	UBERON:0012249	94.23	gold quality
granulocyte	CL:0000094	94.19	gold quality
left testis	UBERON:0004533	94.19	gold quality
endocervix	UBERON:0000458	94.18	gold quality
ganglionic eminence	UBERON:0004023	94.03	gold quality
sural nerve	UBERON:0015488	94.02	gold quality
left ovary	UBERON:0002119	94.01	gold quality
skin of abdomen	UBERON:0001416	93.95	gold quality
skin of leg	UBERON:0001511	93.95	gold quality
right testis	UBERON:0004534	93.69	gold quality
aorta	UBERON:0000947	93.68	gold quality
right ovary	UBERON:0002118	93.68	gold quality
body of stomach	UBERON:0001161	93.66	gold quality
thyroid gland	UBERON:0002046	93.62	gold quality
adenohypophysis	UBERON:0002196	93.47	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.03
E-GEOD-100618	no	256.72

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

63 targets.

Target	Regulation
ABL1
ACTL6A
APOC3
AR
BIRC2
BMP4
CD4
CD44
CD74
CD82
CDK1
CDKN1A
CLASP1
COL2A1	Activation
CREBBP
CSF2
CXCL8
DNTTIP2
EIF3K
EP400
ERCC1	Activation
GMPS	Repression
H2AZ1
HDC	Repression
HSPA4
IFNG
IL2	Unknown
ITPR1
KAT5
KLK3

Upstream regulators (CollecTRI, top): AR, BRD4, CLOCK, EOMES, JMJD6, KAT5, NR4A1, SP1, USF1

miRNA regulators (miRDB)

15 targeting KAT5, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-6852-3P	98.54	67.60	1468
HSA-MIR-6867-3P	98.12	66.07	1305
HSA-MIR-4287	97.55	67.24	1247
HSA-MIR-4685-3P	97.55	67.35	1255
HSA-MIR-3909	97.55	66.78	887
HSA-MIR-1226-3P	97.51	66.32	1063
HSA-MIR-194-3P	97.36	65.96	1027
HSA-MIR-6782-5P	96.45	64.42	612
HSA-MIR-6735-3P	96.10	63.81	600
HSA-MIR-6726-5P	95.97	63.72	841
HSA-MIR-920	95.97	63.95	811
HSA-MIR-4300	95.85	64.56	1003
HSA-MIR-5591-5P	95.85	64.76	1002

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 69.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Androgen receptor, Tip60, and HDAC1 form a trimeric complex upon the endogenous AR-responsive PSA promoter, acetylation and deacetylation of the AR is an important mechanism for regulating transcriptional activity. (PMID:11994312)
• gamma secretase cleavage of APP may contribute to Alzheimer’s disease-related neurodegeneration [GAMMA SECRETASE] (PMID:12032152)
• Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-kappaB and beta-amyloid precursor protein. (PMID:12150997)
• Tip60 acetyltransferase activity is controlled by G(2)/M-dependent phosphorylation (PMID:12468530)
• TIP60 has a role in contributing to histone acetylation in response to mitogenic signals (PMID:12776177)
• Data show that NuA4 complexes, including Tip60 and its splice variant Tip60b/PLIP, are indeed present in human cells. (PMID:14966270)
• HIV-1 Tat down-regulates telomerase activity in the nucleus of CD4-positive T-cells. (PMID:15017382)
• E2F1-dependent recruitment of Tip60 to chromatin occurred in late G(1) (PMID:15121871)
• Tip60 plays a double role in the p53 pathway: under normal growth conditions, Tip60 contributes to maintain a basal pool of p53 by interfering with its degradation; following DNA damage, Tip60 functions as p53 co-activator (PMID:15310756)
• TIP60 acetylates c-myc oncoprotein and regulates its function by altering its rate of degradation. (PMID:15572685)
• Results identify YL1 as a subunit of the TRRAP/TIP60 HAT complex, and also as a component of a novel mammalian multiprotein complex that includes the SNF2-related helicase SRCAP. (PMID:15647280)
• We conclude that PLIP may cause cells to exit from the cell cycle after the S phase and may function as part of a G2/M checkpoint mechanism. (PMID:15985650)
• Neutralization of Tip60 by HIV-1 Tat inhibits the apoptotic response of cells to a genotoxic treatment (PMID:16001085)
• DNA damage induces the rapid acetylation of ATM, dependent on the Tip60 histone acetyltransferase; activation of Tip60 by DNA damage and the recruitment of the ATM-Tip60 complex to sites of DNA damage is independent of ATM’s kinase activity. (PMID:16141325)
• HAT cofactor Trrap and Tip60 HAT bind to the chromatin surrounding sites of DNA double-strand breaks (DSBs).The cells may use the same basic mechanism involving HAT complexes to regulate distinct cellular processes, such as transcription and DNA repair. (PMID:16341205)
• Tip60 and p400 play distinct roles in DNA damage-induced apoptosis and underline the importance of the Tip60 complex and its regulation in the proper control of cell fate. (PMID:16601686)
• ability of Tip60 to regulate the activation of both ATM and DNA-PKcs in response to DNA damage demonstrates that Tip60 is a key component of the DNA damage-signaling network (PMID:16603769)
• Here, we describe how TIP60 is a multifunctional enzyme involved in multiple nuclear transactions[review] (PMID:16698308)
• The activation of ATM/ATR/CHK signaling pathways contributes to this G2 checkpoint and highlight the interrelated roles of p14ARF and the Tip60 protein in the initiation of this DNA damage-signaling cascade. (PMID:16705183)
• Authors hypothesize that the HIV-1 TaT interacting protein can fuse with the PDLIM7 protein and that the fusion proteins could be easily transduced through biological membranes and have biological activity. (PMID:17126496)
• Tip60-dependent acetylation of p53 at K120 modulates the decision between cell-cycle arrest and apoptosis, and it reveals that the DNA-binding core domain is an important target for p53 regulation by posttranslational modifications. (PMID:17189186)
• Notch1 intracellular domain plays the role of a negative regulator in AICD signaling via the disruption of the AICD-Fe65-Tip60 trimeric complex. (PMID:17368826)
• Tip60 effects vary between different PLAGL2 target gene promoters, suggesting that Tip60 is a novel promoter-specific coactivator of PLAGL2. (PMID:17551969)
• HTATIP acts as a negative regulator of NOTCH1 signaling by means of acetylation. (PMID:17636029)
• Data suggest that the sequential acetylation and ubiquitination of H2AX by TIP60-UBC13 promote enhanced histone dynamics, which in turn stimulate a DNA damage response. (PMID:17709392)
• in both mouse and human, Tip60 has a haplo-insufficient tumour suppressor activity that is independent from-but not contradictory with-its role within the ARF-p53 pathway (PMID:17728759)
• Regulation of the subcellular localisation of Tat-interactive protein 60 kDa via phosphorylation provides a novel means of controlling Tat-interactive protein 60 kDa function. (PMID:17851107)
• NPAT recruits the TRRAP-Tip60 complex to histone gene promoters to coordinate the transcriptional activation of multiple histone genes during the G(1)/S-phase transition (PMID:17967892)
• ETV6 interacts with TIP60 through a 63 amino acids region located in the central domain of ETV6 between the pointed and the ets domain. (PMID:17980166)
• Rev-erbbeta modulates the apoCIII gene expression by recruiting different transcription co-activator or co-repressor. (PMID:17996965)
• HIV-1 Tat-interacting protein 60 (Tip60) as a novel positive regulator of PPARgamma transcriptional activity. (PMID:18096664)
• a functional synergism between C/EBPalpha and HTATIP in myeloid differentiation (PMID:18239623)
• chromatin remodeling protein, Tip60, interacts directly with the FANCD2 protein (PMID:18263878)
• Study found that Tip60 is capable of selectively inhibiting the Mdm2-mediated conjugation of Nedd8 to p53, whereas it did not affect p53 ubiquitination; hence, the two different E3 ligase activities of Mdm2 can be regulated individually. (PMID:18264029)
• Rvb1 is critical for the dephosphorylation of phospho-H2AX due to the role of Rvb1 in maintaining the histone acetyltransferase activity of Tip60/NuA4 (PMID:18285460)
• analysis of regulation of ATM activation by ATF2-dependent control of TIP60 stability and activity (PMID:18397884)
• review of roles of cebpa and tip60 in genetics of leukemiogenesis (PMID:18414493)
• HAT gene expression is required for cisplatin resistance and Clock and Tip60 regulate not only transcription, but also DNA repair, through periodic histone acetylation (PMID:18458078)
• contribute to a functional linkage between TIP60 and p73beta through MDM2 in the transcriptional regulation of cellular apoptosis (PMID:18499675)
• Tip60 enables ultraviolet rays (UV)-induced dna damage response (DDR) signaling even in the absence of p53, whereas preaccumulated p53 suppresses UV-induced DDR by reducing the levels of BRCA1. (PMID:18625847)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Kat5	ENSMUSG00000024926
rattus_norvegicus	Kat5	ENSRNOG00000061012
drosophila_melanogaster	tth	FBGN0030502
drosophila_melanogaster	d4	FBGN0033015
caenorhabditis_elegans		WBGENE00016200

Paralogs (9): DPF1 (ENSG00000011332), RSF1 (ENSG00000048649), KAT6A (ENSG00000083168), KAT8 (ENSG00000103510), PHF10 (ENSG00000130024), DPF2 (ENSG00000133884), KAT7 (ENSG00000136504), KAT6B (ENSG00000156650), DPF3 (ENSG00000205683)

Protein

Protein identifiers

Histone acetyltransferase KAT5 — Q92993 (reviewed: Q92993)

Alternative names: 60 kDa Tat-interactive protein, Histone acetyltransferase HTATIP, Lysine acetyltransferase 5, Protein 2-hydroxyisobutyryltransferase KAT5, Protein acetyltransferase KAT5, Protein crotonyltransferase KAT5, Protein lactyltransferase KAT5, cPLA(2)-interacting protein

All UniProt accessions (8): Q92993, E9PJI1, E9PMG8, E9PRL6, E9PRM3, E9PRS1, H0YEG3, H0YEP0

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic subunit of the NuA4 histone acetyltransferase complex, a multiprotein complex involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H2A and H4. Histone acetylation alters nucleosome-DNA interactions and promotes interaction of the modified histones with other proteins which positively regulate transcription. The NuA4 histone acetyltransferase complex is required for the activation of transcriptional programs associated with proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair. The NuA4 complex plays a direct role in repair of DNA double-strand breaks (DSBs) by promoting homologous recombination (HR): the complex inhibits TP53BP1 binding to chromatin via MBTD1, which recognizes and binds histone H4 trimethylated at ‘Lys-20’ (H4K20me), and KAT5 that catalyzes acetylation of ‘Lys-15’ of histone H2A (H2AK15ac), thereby blocking the ubiquitination mark required for TP53BP1 localization at DNA breaks. Also involved in DSB repair by mediating acetylation of ‘Lys-5’ of histone H2AX (H2AXK5ac), promoting NBN/NBS1 assembly at the sites of DNA damage. The NuA4 complex plays a key role in hematopoietic stem cell maintenance and is required to maintain acetylated H2A.Z/H2AZ1 at MYC target genes. The NuA4 complex is also required for spermatid development by promoting acetylation of histones: histone hyperacetylation is required for histone replacement during the transition from round to elongating spermatids. Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AZ1 from the nucleosome. Also acetylates non-histone proteins, such as BMAL1, ATM, AURKB, CHKA, CGAS, ERCC4/XPF, LPIN1, TP53/p53, NDC80/HEC1, NR1D2, RAN, SOX4, FOXP3, SQSTM1, ULK1 and RUBCNL/Pacer. Directly acetylates and activates ATM. Promotes nucleotide excision repair (NER) by mediating acetylation of ERCC4/XPF, thereby promoting formation of the ERCC4-ERCC1 complex. Relieves NR1D2-mediated inhibition of APOC3 expression by acetylating NR1D2. Acts as a regulator of regulatory T-cells (Treg) by catalyzing FOXP3 acetylation, thereby promoting FOXP3 transcriptional repressor activity. Involved in skeletal myoblast differentiation by mediating acetylation of SOX4. Catalyzes acetylation of APBB1/FE65, increasing its transcription activator activity. Promotes transcription elongation during the activation phase of the circadian cycle by catalyzing acetylation of BMAL1, promoting elongation of circadian transcripts. Together with GSK3 (GSK3A or GSK3B), acts as a regulator of autophagy: phosphorylated at Ser-86 by GSK3 under starvation conditions, leading to activate acetyltransferase activity and promote acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer. Acts as a regulator of the cGAS-STING innate antiviral response by catalyzing acetylation the N-terminus of CGAS, thereby promoting CGAS DNA-binding and activation. Also regulates lipid metabolism by mediating acetylation of CHKA or LPIN1. Promotes lipolysis of lipid droplets following glucose deprivation by mediating acetylation of isoform 1 of CHKA, thereby promoting monomerization of CHKA and its conversion into a tyrosine-protein kinase. Acts as a regulator of fatty-acid-induced triacylglycerol synthesis by catalyzing acetylation of LPIN1, thereby promoting the synthesis of diacylglycerol. In addition to protein acetyltransferase, can use different acyl-CoA substrates, such as (2E)-butenoyl-CoA (crotonyl-CoA), S-lactoyl-CoA (lactyl-CoA) and 2-hydroxyisobutanoyl-CoA (2-hydroxyisobutyryl-CoA), and is able to mediate protein crotonylation, lactylation and 2-hydroxyisobutyrylation, respectively. Acts as a key regulator of chromosome segregation and kinetochore-microtubule attachment during mitosis by mediating acetylation or crotonylation of target proteins. Catalyzes acetylation of AURKB at kinetochores, increasing AURKB activity and promoting accurate chromosome segregation in mitosis. Acetylates RAN during mitosis, promoting microtubule assembly at mitotic chromosomes. Acetylates NDC80/HEC1 during mitosis, promoting robust kinetochore-microtubule attachment. Catalyzes crotonylation of MAPRE1/EB1, thereby ensuring accurate spindle positioning in mitosis. Catalyzes lactylation of NBN/NBS1 in response to DNA damage, thereby promoting DNA double-strand breaks (DSBs) via homologous recombination (HR). (Microbial infection) Catalyzes the acetylation of flavivirus NS3 protein to modulate their RNA-binding and -unwinding activities leading to facilitate viral replication.

Subunit / interactions. Component of the NuA4 histone acetyltransferase complex which contains the catalytic subunit KAT5/TIP60 and the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41, VPS72/YL1 and MEAF6. KAT5/TIP60, EPC1, and ING3 together constitute a minimal HAT complex termed Piccolo NuA4. The NuA4 complex interacts with MYC. Interacts with ATM. Interacts with JADE1. Interacts with PLA2G4A/CPLA2, EDNRA and HDAC7. Interacts with the cytoplasmic tail of APP and APBB1/FE65. Interacts with TRIM24 and TRIM68. Forms a complex with SENP6 and UBE2I in response to UV irradiation. Identified in a complex with HINT1. Interacts with ATF2 and CUL3. Interacts with NR1D2 (via N-terminus). Component of a SWR1-like complex. Interacts with FOXP3. Interacts with ZBTB49. Interacts with SRF. Interacts with ATF3; promoting autoacetylation and deubiquitination by USP7. Interacts with EP300/p300; interaction promotes KAT5 autoacetylation. Interacts with PRKDC; interaction is impaired following KAT5 sumoylation. Interacts with GPR50. Interacts with NME3; this interaction enables recruitment of NME3 at DNA damage sites where it plays a role in the repair of DNA. (Microbial infection) Interacts with HIV-1 TAT.

Subcellular location. Nucleus. Chromosome. Cytoplasm. Centromere. Kinetochore. Cytoskeleton. Spindle pole. Nucleolus. Perinuclear region Cytoplasm.

Post-translational modifications. Phosphorylated on Ser-86 and Ser-90; enhanced during G2/M phase. The phosphorylated form has a higher activity. Phosphorylation at Ser-90 by CDK1 or CDK9 is a prerequisite for phosphorylation at Ser-86 by GSK3. Phosphorylation at Ser-86 by GSK3 (GSK3A or GSK3B) activates acetyltransferase and acyltransferase activities. Phosphorylation at Ser-90 by CDK9 promotes KAT5 recruitment to chromatin. Phosphorylation by VRK1 following DNA damage promotes KAT5 association with chromatin and histone acetyltransferase activity. Autoacetylated. Autoacetylation is required for histone acetyltransferase activity. Autoacetylation at Lys-327 is facilitated by interaction with EP300/p300: it prevents ubiquitination and subsequent degradation by the proteasome and promotes acetylation of target proteins. Deacetylated by HDAC3 and SIRT1. Deacetylation by HDAC3 promotes its ubiquitination and cytoplasmic localization. Sumoylated by UBE2I at Lys-430 and Lys-451, leading to increase of its histone acetyltransferase activity in UV-induced DNA damage response, as well as its translocation to nuclear bodies. Sumoylation with SUMO2 by PIAS4 at Lys-430 promotes repair of DNA double-strand breaks (DSBs) via homologous recombination (HR). Sumoylation by PIAS4 impairs interaction with PRKDC, inhibiting non-homologous end joining (NHEJ)-mediated repair of DSBs, thereby facilitating HR. Desumoylated by SENP3. Ubiquitinated by MDM2, leading to its proteasome-dependent degradation. Ubiquitination is prevented by autoacetylation at Lys-327. Ubiquitinated following deacetylation by HDAC3, leading to cytoplasmic localization. Deubiquitinated by USP7 following interaction with ATF3, promoting its stabilization. (Microbial infection) In case of HIV-1 infection, interaction with the viral Tat protein leads to KAT5 polyubiquitination and targets it to degradation.

Disease relevance. Neurodevelopmental disorder with dysmorphic facies, sleep disturbance, and brain abnormalities (NEDFASB) [MIM:619103] A neurodevelopmental disorder characterized by severe global developmental delay, intellectual disability, poor or absent language, behavioral abnormalities, severe sleep disturbance, seizures, cerebral malformations, and craniofacial dysmorphism. Progressive cerebellar atrophy is also observed. Additional features may include genitourinary tract anomalies, hearing loss, and mild distal skeletal defects. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Acyltransferase and acetyltransferase activities are activated by phosphorylation and autoacetylation. Autoacetylation activates the histone acetyltransferase activity.

Similarity. Belongs to the MYST (SAS/MOZ) family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q92993-1	2	yes
Q92993-2	1, PLIP
Q92993-3	3
Q92993-4	4

RefSeq proteins (4): NP_001193762, NP_006379, NP_874368, NP_874369* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000953	Chromo/chromo_shadow_dom	Domain
IPR002717	HAT_MYST-type	Domain
IPR016181	Acyl_CoA_acyltransferase	Homologous_superfamily
IPR016197	Chromo-like_dom_sf	Homologous_superfamily
IPR025995	Tudor-knot	Domain
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR040706	Zf-MYST	Domain
IPR050603	MYST_HAT	Family

Pfam: PF01853, PF11717, PF17772

Enzyme classification (BRENDA):

• EC 2.3.1.48 — histone acetyltransferase (BRENDA: 41 organisms, 681 substrates, 1134 inhibitors, 140 Km, 96 kcat entries)

Substrate kinetics (BRENDA)

27 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ACETYL-COA	0.0002–0.046	51
HISTONE H3	0.007–2.09	23
HISTONE H4	—	11
HISTONE H4 PEPTIDE	0.0208–0.197	7
HISTONE	0.075–1.4	6
HISTONE H3 TAIL PEPTIDE	0.044–0.112	4
PICCOLONUA4 PEPTIDE	0.135–0.372	4
3-AZIDOPROPIONYL-COA	0.0002–0.0086	3
4-PENTYNOYL-COA	0.0009–0.0859	3
SPERMIDINE	0.18–0.27	3
5-HEXYNOYL-COA	0.0006–0.0117	2
6-HEPTYNOYL-COA	0.0003–0.0237	2
HISTONE H3-PEPTIDE	0.05–0.49	2
PROTEIN P53	1.28–4.63	2
3-AZIDOPROPANOYL-COA	0.0103	1

Catalyzed reactions (Rhea), 5 shown:

• L-lysyl-[histone] + acetyl-CoA = N(6)-acetyl-L-lysyl-[histone] + CoA + H(+) (RHEA:21992)
• 2-hydroxyisobutanoyl-CoA + L-lysyl-[protein] = N(6)-(2-hydroxyisobutanoyl)-L-lysyl-[protein] + CoA + H(+) (RHEA:24180)
• L-lysyl-[protein] + acetyl-CoA = N(6)-acetyl-L-lysyl-[protein] + CoA + H(+) (RHEA:45948)
• (2E)-butenoyl-CoA + L-lysyl-[protein] = N(6)-(2E)-butenoyl-L-lysyl-[protein] + CoA + H(+) (RHEA:53908)
• (S)-lactoyl-CoA + L-lysyl-[protein] = N(6)-[(S)-lactoyl]-L-lysyl-[protein] + CoA + H(+) (RHEA:61996)

UniProt features (84 total): mutagenesis site 17, strand 17, helix 13, modified residue 11, binding site 4, sequence variant 4, cross-link 3, region of interest 3, domain 2, splice variant 2, sequence conflict 2, turn 2, chain 1, zinc finger region 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2OU2	X-RAY DIFFRACTION	2.3
4QQG	X-RAY DIFFRACTION	2.8
2EKO	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92993-F1	76.76	0.50

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 403 (proton donor/acceptor)

Ligand- & substrate-binding residues (4): 377–383; 407; 416; 370–372

Post-translational modifications (14): 52, 86, 90, 104, 120, 148, 150, 187, 189, 199, 327, 430, 430, 451

Mutagenesis-validated functional residues (17):

Position	Phenotype
86	reduced phosphorylation. abolishes phosphorylation; when associated with a-90. reduced histone acetyltransferase activit
90	reduced phosphorylation, leading to reduced protein acetyltransferase activity. abolishes phosphorylation; when associat
90	mimics phosphorylation, promoting protein acetyltransferase activity.
104	impaired acetylation, leading to reduced histone acetyltransferase activity. in k6r; abolished autoacetylation; when ass
120	in k6r; abolished autoacetylation; when associated with r-104, r-148, r-150, r-187 and r-189.
148	in k6r; abolished autoacetylation; when associated with r-104, r-120, r-150, r-187 and r-189.
150	in k6r; abolished autoacetylation; when associated with r-104, r-120, r-148, r-187 and r-189.
187	in k6r; abolished autoacetylation; when associated with r-104, r-120, r-148, r-150 and r-189.
189	in k6r; abolished autoacetylation; when associated with r-104, r-120, r-148, r-150 and r-187.
254	does not affect phosphorylation; when associated with a-257.
257	does not affect phosphorylation; when associated with a-254.
327	mimics acetylation; promoting interaction with foxp3 and subsequent acetylation.
327	decreased autoacetylation; leading to decreased acetyltransferase activity and ability to acetylate foxp3.
377–380	in kat5(qg/ee) mutant; abolished acetyltransferase activity. impaired ability to activate cgas.
380	loss of function. does not affect phosphorylation.
430	abrogates sumoylation. abolished sumoylation by pias4, promoting interaction with prkdc, leading to decreased repair of
451	abrogates sumoylation.

Function

Pathways and Gene Ontology

Reactome pathways

52 pathways

ID	Pathway
R-HSA-201722	Formation of the beta-catenin:TCF transactivating complex
R-HSA-2559586	DNA Damage/Telomere Stress Induced Senescence
R-HSA-3214847	HATs acetylate histones
R-HSA-5685938	HDR through Single Strand Annealing (SSA)
R-HSA-5685942	HDR through Homologous Recombination (HRR)
R-HSA-5693548	Sensing of DNA Double Strand Breaks
R-HSA-5693554	Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)
R-HSA-5693565	Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks
R-HSA-5693568	Resolution of D-loop Structures through Holliday Junction Intermediates
R-HSA-5693571	Nonhomologous End-Joining (NHEJ)
R-HSA-5693579	Homologous DNA Pairing and Strand Exchange
R-HSA-5693607	Processing of DNA double-strand break ends
R-HSA-5693616	Presynaptic phase of homologous DNA pairing and strand exchange
R-HSA-6804756	Regulation of TP53 Activity through Phosphorylation
R-HSA-69473	G2/M DNA damage checkpoint
R-HSA-9018519	Estrogen-dependent gene expression
R-HSA-9701192	Defective homologous recombination repair (HRR) due to BRCA1 loss of function
R-HSA-9704331	Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function
R-HSA-9704646	Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function
R-HSA-9709570	Impaired BRCA2 binding to RAD51
R-HSA-9709603	Impaired BRCA2 binding to PALB2
R-HSA-9733709	Cardiogenesis
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-1640170	Cell Cycle
R-HSA-1643685	Disease
R-HSA-195721	Signaling by WNT
R-HSA-201681	TCF dependent signaling in response to WNT
R-HSA-212436	Generic Transcription Pathway
R-HSA-2262752	Cellular responses to stress

MSigDB gene sets: 565 (showing top): GOBP_CIRCADIAN_RHYTHM, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_CHROMOSOME_ORGANIZATION, GOBP_ESTABLISHMENT_OF_SPINDLE_ORIENTATION, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_ATTACHMENT_OF_SPINDLE_MICROTUBULES_TO_KINETOCHORE, GOBP_REGULATION_OF_DNA_RECOMBINATION, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_RESPONSE_TO_ESTRADIOL

GO Biological Process (66): negative regulation of transcription by RNA polymerase II (GO:0000122), establishment of mitotic spindle orientation (GO:0000132), double-strand break repair via homologous recombination (GO:0000724), nucleotide-excision repair (GO:0006289), double-strand break repair (GO:0006302), apoptotic process (GO:0006915), DNA damage response (GO:0006974), spermatid development (GO:0007286), response to ionizing radiation (GO:0010212), positive regulation of autophagy (GO:0010508), positive regulation of triglyceride biosynthetic process (GO:0010867), peptidyl-lysine acetylation (GO:0018394), neural tube development (GO:0021915), neurogenesis (GO:0022008), DNA damage response, signal transduction by p53 class mediator (GO:0030330), negative regulation of interleukin-2 production (GO:0032703), sperm DNA condensation (GO:0035092), cellular response to glucose starvation (GO:0042149), positive regulation of circadian rhythm (GO:0042753), regulation of apoptotic process (GO:0042981), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), innate immune response (GO:0045087), positive regulation of innate immune response (GO:0045089), positive regulation of regulatory T cell differentiation (GO:0045591), positive regulation of myoblast differentiation (GO:0045663), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of cell cycle (GO:0051726), positive regulation of mitotic sister chromatid segregation (GO:0062033), cellular response to glucose stimulus (GO:0071333), cellular response to estradiol stimulus (GO:0071392), cellular senescence (GO:0090398), DNA repair-dependent chromatin remodeling (GO:0140861), positive regulation of protein acetylation (GO:1901985), regulation of hematopoietic stem cell differentiation (GO:1902036), positive regulation of attachment of mitotic spindle microtubules to kinetochore (GO:1902425), positive regulation of double-strand break repair via homologous recombination (GO:1905168), positive regulation of aggrephagy (GO:1905337), lipid droplet disassembly (GO:1905691)

GO Molecular Function (19): chromatin binding (GO:0003682), transcription coactivator activity (GO:0003713), histone acetyltransferase activity (GO:0004402), zinc ion binding (GO:0008270), histone H4 acetyltransferase activity (GO:0010485), acetyltransferase activity (GO:0016407), histone H2A acetyltransferase activity (GO:0043998), histone H2AK5 acetyltransferase activity (GO:0043999), histone H4K16 acetyltransferase activity (GO:0046972), protein-lysine-acetyltransferase activity (GO:0061733), peptide 2-hydroxyisobutyryltransferase activity (GO:0106226), peptide lactyltransferase (CoA-dependent) activity (GO:0120300), peptide crotonyltransferase activity (GO:0140064), peptide butyryltransferase activity (GO:0140065), DNA-binding transcription factor binding (GO:0140297), protein binding (GO:0005515), transferase activity (GO:0016740), acyltransferase activity (GO:0016746), metal ion binding (GO:0046872)

GO Cellular Component (22): kinetochore (GO:0000776), chromatin (GO:0000785), nucleosome (GO:0000786), Swr1 complex (GO:0000812), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), piccolo histone acetyltransferase complex (GO:0032777), NuA4 histone acetyltransferase complex (GO:0035267), site of double-strand break (GO:0035861), perinuclear region of cytoplasm (GO:0048471), mitotic spindle pole (GO:0097431), histone acetyltransferase complex (GO:0000123), chromosome, centromeric region (GO:0000775), spindle pole (GO:0000922), chromosome (GO:0005694), cytoskeleton (GO:0005856), nuclear lumen (GO:0031981), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	3
DNA Double Strand Break Response	2
Resolution of D-Loop Structures	2
Defective homologous recombination repair (HRR) due to PALB2 loss of function	2
TCF dependent signaling in response to WNT	1
Cellular Senescence	1
Chromatin modifying enzymes	1
DNA Double-Strand Break Repair	1
HDR through Homologous Recombination (HRR)	1
Homologous DNA Pairing and Strand Exchange	1
Regulation of TP53 Activity	1
G2/M Checkpoints	1
ESR-mediated signaling	1
Diseases of DNA Double-Strand Break Repair	1
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
acyltransferase activity, transferring groups other than amino-acyl groups	5
intracellular membraneless organelle	4
DNA repair	2
nervous system development	2
binding	2
histone acetyltransferase activity	2
chromatin	2
nuclear lumen	2
protein-containing complex	2
cytoplasm	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
mitotic cell cycle	1
establishment of mitotic spindle localization	1
establishment of spindle orientation	1
recombinational repair	1
double-strand break repair	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cellular response to stress	1
germ cell development	1
spermatid differentiation	1
response to radiation	1
autophagy	1
positive regulation of catabolic process	1
regulation of autophagy	1
regulation of triglyceride biosynthetic process	1
triglyceride biosynthetic process	1
positive regulation of lipid biosynthetic process	1
positive regulation of triglyceride metabolic process	1
protein acetylation	1
peptidyl-lysine modification	1
tube development	1
chordate embryonic development	1
epithelium development	1
cell differentiation	1
signal transduction in response to DNA damage	1

Protein interactions and networks

STRING

3232 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KAT5	APBB1	O00213	998
KAT5	EP400	Q96L91	998
KAT5	TRRAP	Q9Y4A5	997
KAT5	HDAC9	Q9UKV0	987
KAT5	FOXP3	Q9BZS1	986
KAT5	KAT2A	Q92830	982
KAT5	KAT2B	Q92831	982
KAT5	RUVBL2	Q9Y230	981
KAT5	RUVBL1	P82276	979
KAT5	APP	P05067	973
KAT5	HDAC7	Q8WUI4	969
KAT5	TP53	P04637	961
KAT5	MORF4L1	Q9UBU8	959
KAT5	HDAC1	Q13547	955
KAT5	SRCAP	Q6ZRS2	945

IntAct

868 interactions, top by confidence:

A	B	Type	Score
TP53		psi-mi:“MI:0914”(association)	0.930
RUVBL1	KAT5	psi-mi:“MI:0915”(physical association)	0.890
MBTD1	YEATS4	psi-mi:“MI:0914”(association)	0.730
MBTD1	MORF4L2	psi-mi:“MI:0914”(association)	0.730
STX11	KAT5	psi-mi:“MI:0915”(physical association)	0.720
KAT5	ODC1	psi-mi:“MI:0915”(physical association)	0.720
HMBOX1	KAT5	psi-mi:“MI:0915”(physical association)	0.720
LZTS2	KAT5	psi-mi:“MI:0915”(physical association)	0.720
KAT5	DNAAF6	psi-mi:“MI:0915”(physical association)	0.720
IKZF3	KAT5	psi-mi:“MI:0915”(physical association)	0.720
KAT5	STX11	psi-mi:“MI:0915”(physical association)	0.720
ODC1	KAT5	psi-mi:“MI:0915”(physical association)	0.720
KAT5	LZTS2	psi-mi:“MI:0915”(physical association)	0.720
ATXN1	KAT5	psi-mi:“MI:0915”(physical association)	0.710
KAT5	ATXN1	psi-mi:“MI:0915”(physical association)	0.710
KAT5	GMCL1	psi-mi:“MI:0915”(physical association)	0.700
KAT5	ZBTB8A	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (733): KAT5 (Affinity Capture-Western), KAT5 (Two-hybrid), KAT5 (Two-hybrid), KAT5 (Two-hybrid), KAT5 (Two-hybrid), KAT5 (Two-hybrid), KAT5 (Two-hybrid), KAT5 (Two-hybrid), KAT5 (Two-hybrid), KAT5 (Two-hybrid), KAT5 (Two-hybrid), KAT5 (Two-hybrid), KAT5 (Two-hybrid), KAT5 (Two-hybrid), IKZF3 (Two-hybrid)

ESM2 similar proteins: A1L251, A3KPF2, A7SLX5, F4IDQ6, F4IM84, F4INY4, F4JZC2, F4KH86, O13648, O15056, O46043, O55207, O60157, P46580, P50244, Q08A71, Q09357, Q0WVD6, Q1EHT7, Q22949, Q39677, Q43820, Q45EK7, Q5F3R2, Q5RBG4, Q60K16, Q61J97, Q6C710, Q6GPQ5, Q75B12, Q7YTB0, Q84W92, Q8BX80, Q8CHK4, Q8CIG3, Q8LI34, Q8NB78, Q92993, Q96286, Q96471

Diamond homologs: C8VBH4, K8ERR8, O02193, O94446, O95251, P0CP02, P0CP03, P34218, P40963, Q08649, Q10325, Q2UMQ5, Q4IEV4, Q4P3S3, Q4WHG1, Q5A7Q2, Q5RBG4, Q5SVQ0, Q5TKR9, Q5XI06, Q6BU95, Q6C710, Q6CKE9, Q6FPH9, Q75BY2, Q7S9B6, Q810T5, Q8BRB7, Q8BZ21, Q8CHK4, Q8LI34, Q8WML3, Q8WYB5, Q92794, Q92993, Q960X4, Q99MK2, Q9D1P2, Q9FLF7, Q9H7Z6

SIGNOR signaling

19 interactions.

A	Effect	B	Mechanism
CDK1	up-regulates	KAT5	phosphorylation
KAT5	down-regulates	NOTCH1	acetylation
KAT5	down-regulates	SRSF2	acetylation
GSK3B	up-regulates	KAT5	phosphorylation
KAT5	“up-regulates activity”	MYOD1	binding
CyclinB/CDK1	“up-regulates activity”	KAT5	phosphorylation
KAT5	“down-regulates activity”	H4C1	acetylation
KAT5	“up-regulates activity”	CHKA	acetylation
KAT5	“form complex”	“NuA4 complex”	binding
MDM2	“down-regulates quantity by destabilization”	KAT5	polyubiquitination
ABL1	“down-regulates activity”	KAT5	phosphorylation
MAPK14	“up-regulates activity”	KAT5	phosphorylation
PRKCE	“up-regulates activity”	KAT5	phosphorylation
KAT5	“up-regulates activity”	ATM	acetylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 90 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
regulation of double-strand break repair	5	35.9×	7e-05
positive regulation of double-strand break repair via homologous recombination	6	28.4×	4e-05
regulation of apoptotic process	7	7.2×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

155 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	111
Likely benign	12
Benign	8

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
987964	NM_182710.3(KAT5):c.257G>A (p.Arg86His)	Pathogenic
987965	NM_182710.3(KAT5):c.1204T>A (p.Cys402Ser)	Pathogenic
987966	NM_182710.3(KAT5):c.1336T>G (p.Ser446Ala)	Pathogenic
3895531	NM_182710.3(KAT5):c.256C>T (p.Arg86Cys)	Likely pathogenic

SpliceAI

1960 predictions. Top by Δscore:

Variant	Effect	Δscore
11:65712244:G:GT	donor_gain	1.0000
11:65712437:A:G	donor_gain	1.0000
11:65712441:GTGGC:G	donor_gain	1.0000
11:65712442:TGGC:T	donor_gain	1.0000
11:65712443:GGCG:G	donor_gain	1.0000
11:65712444:GC:G	donor_gain	1.0000
11:65712446:G:GG	donor_gain	1.0000
11:65712763:T:G	acceptor_gain	1.0000
11:65712764:A:AG	acceptor_gain	1.0000
11:65712764:AGC:A	acceptor_loss	1.0000
11:65712765:G:GA	acceptor_gain	1.0000
11:65712765:GC:G	acceptor_gain	1.0000
11:65712765:GCC:G	acceptor_gain	1.0000
11:65712765:GCCCT:G	acceptor_gain	1.0000
11:65712830:TGACT:T	donor_gain	1.0000
11:65712831:GACT:G	donor_gain	1.0000
11:65712831:GACTG:G	donor_gain	1.0000
11:65712832:ACT:A	donor_gain	1.0000
11:65712833:CT:C	donor_gain	1.0000
11:65712834:TGT:T	donor_loss	1.0000
11:65712835:G:C	donor_loss	1.0000
11:65712835:G:GG	donor_gain	1.0000
11:65712836:T:G	donor_loss	1.0000
11:65712916:CTACA:C	acceptor_loss	1.0000
11:65712917:TACA:T	acceptor_loss	1.0000
11:65712918:ACAG:A	acceptor_loss	1.0000
11:65712919:CAGT:C	acceptor_loss	1.0000
11:65712920:A:AG	acceptor_gain	1.0000
11:65712920:AG:A	acceptor_loss	1.0000
11:65712921:G:GT	acceptor_gain	1.0000

AlphaMissense

3542 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:65712404:T:C	L13P	1.000
11:65712772:C:A	A29D	1.000
11:65712778:T:A	I31N	1.000
11:65712781:T:C	L32P	1.000
11:65712816:T:G	Y44D	1.000
11:65712820:T:A	V45D	1.000
11:65712822:C:G	H46D	1.000
11:65712825:T:G	Y47D	1.000
11:65712834:T:C	F50L	1.000
11:65712923:C:A	F50L	1.000
11:65712923:C:G	F50L	1.000
11:65712926:C:A	N51K	1.000
11:65712926:C:G	N51K	1.000
11:65712927:A:G	K52E	1.000
11:65712928:A:C	K52T	1.000
11:65712928:A:T	K52I	1.000
11:65712929:A:C	K52N	1.000
11:65712929:A:T	K52N	1.000
11:65712930:C:A	R53S	1.000
11:65712930:C:G	R53G	1.000
11:65712930:C:T	R53C	1.000
11:65712931:G:A	R53H	1.000
11:65712931:G:C	R53P	1.000
11:65712934:T:C	L54P	1.000
11:65712936:G:A	D55N	1.000
11:65712936:G:C	D55H	1.000
11:65712936:G:T	D55Y	1.000
11:65712937:A:C	D55A	1.000
11:65712937:A:G	D55G	1.000
11:65712937:A:T	D55V	1.000

dbSNP variants (sampled 300 via entrez): RS1000415536 (11:65718789 C>CT), RS1000948431 (11:65714683 C>T), RS1001022722 (11:65712088 G>A), RS1001530239 (11:65717790 A>G), RS1001622169 (11:65719267 A>C,G), RS1002184159 (11:65718371 C>A), RS1002252797 (11:65718130 C>G,T), RS1002845271 (11:65714670 C>A,T), RS1003237150 (11:65711327 T>C), RS1003237993 (11:65719579 C>A,T), RS1003243090 (11:65711637 G>A), RS1003538482 (11:65715051 G>A), RS1003594146 (11:65713406 G>A), RS1003972352 (11:65715403 A>G), RS1004024529 (11:65715639 T>C)

Disease associations

OMIM: gene MIM:601409 | disease phenotypes: MIM:619103, MIM:610329

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with dysmorphic facies, sleep disturbance, and brain abnormalities	Strong	Autosomal dominant

Mondo (4): neurodevelopmental disorder with dysmorphic facies, sleep disturbance, and brain abnormalities (MONDO:0030852), neurodevelopmental disorder (MONDO:0700092), Aicardi-Goutieres syndrome 3 (MONDO:0012471), familial colorectal cancer (MONDO:0023113)

Orphanet (1): Aicardi-Goutières syndrome (Orphanet:51)

HPO phenotypes

40 total (30 of 40 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000076	Vesicoureteral reflux
HP:0000085	Horseshoe kidney
HP:0000154	Wide mouth
HP:0000176	Submucous cleft hard palate
HP:0000179	Thick lower lip vermilion
HP:0000252	Microcephaly
HP:0000303	Mandibular prognathia
HP:0000311	Round face
HP:0000369	Low-set ears
HP:0000414	Bulbous nose
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000540	Hypermetropia
HP:0000733	Motor stereotypy
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001338	Partial agenesis of the corpus callosum
HP:0001629	Ventricular septal defect
HP:0002360	Sleep disturbance
HP:0003577	Congenital onset
HP:0005164	Dysplastic pulmonary valve
HP:0005280	Depressed nasal bridge
HP:0005338	Sparse lateral eyebrow
HP:0006989	Dysplastic corpus callosum
HP:0007018	Attention deficit hyperactivity disorder

GWAS associations

25 associations (top):

Study	Trait	p-value
GCST000649_13	Chronic kidney disease	1.000000e-07
GCST002223_39	HDL cholesterol	3.000000e-08
GCST002481_8	Acne (severe)	3.000000e-11
GCST004232_64	HDL cholesterol levels	4.000000e-10
GCST006166_27	Diastolic blood pressure x alcohol consumption interaction (2df test)	1.000000e-09
GCST006166_95	Diastolic blood pressure x alcohol consumption interaction (2df test)	6.000000e-11
GCST006190_11	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	6.000000e-09
GCST006190_80	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	2.000000e-11
GCST006192_55	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	2.000000e-08
GCST006192_82	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	9.000000e-06
GCST006193_44	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	6.000000e-08
GCST006193_82	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	1.000000e-10
GCST006195_74	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	1.000000e-07
GCST006434_98	Systolic blood pressure x alcohol consumption interaction (2df test)	1.000000e-12
GCST006613_149	Triglycerides	2.000000e-08
GCST006979_402	Heel bone mineral density	6.000000e-16
GCST008059_128	Estimated glomerular filtration rate	2.000000e-34
GCST008916_61	Asthma	4.000000e-11
GCST010002_240	Refractive error	3.000000e-11
GCST010242_1	HDL cholesterol levels	7.000000e-19
GCST010244_224	Triglyceride levels	4.000000e-19
GCST90020024_394	A body shape index	4.000000e-14
GCST90020025_1879	Waist-to-hip ratio adjusted for BMI	1.000000e-15
GCST90020027_1496	Waist-hip index	3.000000e-16
GCST90020029_328	Waist circumference adjusted for body mass index	6.000000e-15

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004329	alcohol drinking
EFO:0006336	diastolic blood pressure
EFO:0006527	smoking status measurement
EFO:0006335	systolic blood pressure
EFO:0004530	triglyceride measurement
EFO:0009270	heel bone mineral density
EFO:0007789	BMI-adjusted waist circumference
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625
C563683	Aicardi-Goutieres Syndrome 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5750 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 32,888 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1213327	COENZYME_A	3	10,084
CHEMBL297453	EPIGALOCATECHIN GALLATE	3	22,804

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — 2.3.1.48 Histone acetyltransferases (HATs)

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
PF-9363	Inhibition	6.38	pIC50
MG149	Inhibition	4.13	pIC50

ChEMBL bioactivities

55 potent at pChembl≥5 of 208 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.16	Ki	70	nM	CHEMBL5993180
6.96	Ki	110	nM	CHEMBL5955544
6.92	Ki	120	nM	CHEMBL5852195
6.89	Ki	130	nM	CHEMBL5886450
6.82	Ki	150	nM	CHEMBL5818085
6.82	Ki	150	nM	CHEMBL5927368
6.75	Ki	180	nM	CHEMBL5998930
6.75	Ki	180	nM	CHEMBL5883288
6.72	Ki	190	nM	CHEMBL5812221
6.70	Ki	200	nM	CHEMBL5941367
6.66	Ki	220	nM	CHEMBL6005841
6.58	Ki	260	nM	CHEMBL5853409
6.57	Ki	270	nM	CHEMBL5959733
6.50	Ki	320	nM	CHEMBL5963038
6.50	Ki	320	nM	CHEMBL5830107
6.43	Ki	370	nM	CHEMBL5723326
6.39	Ki	410	nM	CHEMBL5792825
6.37	Ki	430	nM	CHEMBL5996948
6.28	Ki	530	nM	CHEMBL5857566
6.24	Ki	570	nM	CHEMBL5723326
6.21	Ki	620	nM	CHEMBL5723326
6.21	Ki	610	nM	CHEMBL5723326
6.15	Ki	710	nM	CHEMBL5860247
6.11	Ki	770	nM	CHEMBL5925551
6.10	Ki	800	nM	CHEMBL5993009
6.08	Ki	830	nM	CHEMBL6057979
6.05	IC50	900	nM	CHEMBL4455897
6.01	Ki	980	nM	CHEMBL5871508
5.99	Ki	1030	nM	CHEMBL5924783
5.99	Ki	1030	nM	CHEMBL5867166
5.93	Ki	1170	nM	CHEMBL5847041
5.84	IC50	1430	nM	CHEMBL5632729
5.84	Ki	1440	nM	CHEMBL5779221
5.77	Ki	1710	nM	CHEMBL5980695
5.70	IC50	2000	nM	CHEMBL3774630
5.68	Ki	2070	nM	CHEMBL5785798
5.66	IC50	2200	nM	WM-1119
5.58	IC50	2640	nM	CHEMBL4470091
5.53	Ki	2960	nM	CHEMBL5938038
5.52	Ki	3050	nM	CHEMBL5930092
5.51	Ki	3060	nM	CHEMBL5808891
5.44	Ki	3640	nM	CHEMBL5759534
5.36	Ki	4380	nM	CHEMBL5789111
5.34	Ki	4530	nM	CHEMBL5842425
5.33	Ki	4630	nM	CHEMBL5756543
5.24	Ki	5700	nM	CHEMBL5907267
5.22	Ki	5980	nM	CHEMBL5906744
5.21	Ki	6220	nM	CHEMBL6020167
5.07	Ki	8450	nM	CHEMBL5782689
5.06	IC50	8700	nM	WM-1119

PubChem BioAssay actives

6 with measured affinity, of 91 total; 4 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-[2-(2-fluorophenyl)-2-oxoethyl]quinoline-8-sulfonamide	2138648: Inhibition of full length recombinant human KAT5 catalytic domain using H2A peptide and [3H]-acetyl-coA as substrate incubated for 1 hr by liquid scintillation counter analysis	ic50	1.4300	uM
5-(1,2-thiazol-5-yldisulfanyl)-1,2-thiazole	1282413: Inhibition of recombinant N-terminal His-tagged TIP60 (unknown origin) expressed in baculovirus-infected insect cell system using histone substrate incubated for 10 mins by radiometric filter binding assay in presence of [3H]acetyl-CoA	ic50	2.0000	uM
2-fluoro-N’-naphthalen-2-ylsulfonylbenzohydrazide	2138648: Inhibition of full length recombinant human KAT5 catalytic domain using H2A peptide and [3H]-acetyl-coA as substrate incubated for 1 hr by liquid scintillation counter analysis	ic50	2.6400	uM
2-hydroxy-6-[(8Z,11Z)-pentadeca-8,11,14-trienyl]benzoic acid	367606: Inhibition of TIP60 in human HeLa cell extracts by ELISA	ic50	9.0000	uM

CTD chemical–gene interactions

55 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects folding, decreases reaction, decreases activity, increases reaction, increases expression (+1 more)	3
Estradiol	increases reaction, decreases reaction, increases activity, affects binding	3
Valproic Acid	decreases expression	3
trichostatin A	decreases expression	2
sodium arsenite	decreases expression, decreases reaction, affects methylation, affects binding	2
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases reaction, increases acetylation, increases degradation, decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
Batroxase, Bothrops atrox	increases expression	1
TAK-243	increases sumoylation	1
daidzein	decreases reaction, increases activity	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
pirinixic acid	decreases expression, increases activity, affects binding	1
quercitrin	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
zinc chloride	affects binding, affects reaction	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
coumarin	increases phosphorylation	1
4-aminophenylarsenoxide	affects reaction, affects binding, decreases reaction	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
tamibarotene	increases expression	1
di-n-butylphosphoric acid	affects expression	1
cylindrospermopsin	increases expression	1
2-palmitoylglycerol	increases expression	1
2,3-bis(4-hydroxyphenyl)-propionitrile	increases activity, decreases activity, decreases reaction	1
abrine	increases expression	1
bisphenol S	affects binding, increases reaction	1

ChEMBL screening assays

39 unique, capped per target: 39 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1025546	Binding	Inhibition of recombinant Tip60 (1-513) expressed in Escherichia coli BL21 (DE3) by liquid scintillation	Bisubstrate Inhibitors of the MYST HATs Esa1 and Tip60. — Bioorg Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E0FZ	Ubigene HeLa KAT5 KO	Cancer cell line	Female

Clinical trials (associated diseases)

209 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice