ASF1A

Summary

ASF1A (anti-silencing function 1A histone chaperone, HGNC:20995) is a protein-coding gene on chromosome 6q22.31, encoding Histone chaperone ASF1A (Q9Y294). Histone chaperone that facilitates histone deposition and histone exchange and removal during nucleosome assembly and disassembly.

This gene encodes a member of the H3/H4 family of histone chaperone proteins and is similar to the anti-silencing function-1 gene in yeast. The protein is a key component of a histone donor complex that functions in nucleosome assembly. It interacts with histones H3 and H4, and functions together with a chromatin assembly factor during DNA replication and repair.

Source: NCBI Gene 25842 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 38 total — 6 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes
• MANE Select transcript: NM_014034

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20995
Approved symbol	ASF1A
Name	anti-silencing function 1A histone chaperone
Location	6q22.31
Locus type	gene with protein product
Status	Approved
Aliases	DKFZP547E2110, CIA
Ensembl gene	ENSG00000111875
Ensembl biotype	protein_coding
OMIM	609189
Entrez	25842

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 retained_intron

ENST00000229595, ENST00000511766, ENST00000877924

RefSeq mRNA: 1 — MANE Select: NM_014034 NM_014034

CCDS: CCDS47469

Canonical transcript exons

ENST00000229595 — 4 exons

Exon	Start	End
ENSE00000762824	118905652	118905828
ENSE00001295367	118907402	118909171
ENSE00002043177	118894152	118894522
ENSE00002082499	118900766	118900881

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.42.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.2514 / max 341.5905, expressed in 1803 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
69478	21.3855	1790
69480	3.0827	1298
69477	0.8370	509
69479	0.8003	434
69474	0.4845	252
69476	0.4617	238
69475	0.1997	84

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	99.42	gold quality
secondary oocyte	CL:0000655	99.36	gold quality
adrenal tissue	UBERON:0018303	94.04	gold quality
medial globus pallidus	UBERON:0002477	92.67	gold quality
hair follicle	UBERON:0002073	92.28	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.24	gold quality
ganglionic eminence	UBERON:0004023	92.11	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	91.94	gold quality
biceps brachii	UBERON:0001507	91.62	gold quality
globus pallidus	UBERON:0001875	91.51	gold quality
epithelium of nasopharynx	UBERON:0001951	90.94	gold quality
nasopharynx	UBERON:0001728	90.92	gold quality
ventricular zone	UBERON:0003053	90.60	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	90.55	gold quality
germinal epithelium of ovary	UBERON:0001304	90.53	gold quality
trabecular bone tissue	UBERON:0002483	90.24	gold quality
choroid plexus epithelium	UBERON:0003911	89.95	gold quality
upper leg skin	UBERON:0004262	89.50	gold quality
calcaneal tendon	UBERON:0003701	89.02	gold quality
palpebral conjunctiva	UBERON:0001812	88.97	gold quality
cortical plate	UBERON:0005343	88.70	gold quality
eye	UBERON:0000970	88.65	gold quality
superficial temporal artery	UBERON:0001614	88.47	gold quality
vastus lateralis	UBERON:0001379	88.43	gold quality
embryo	UBERON:0000922	88.28	gold quality
corpus epididymis	UBERON:0004359	88.26	gold quality
tendon	UBERON:0000043	88.06	gold quality
corpus callosum	UBERON:0002336	88.02	gold quality
skin of hip	UBERON:0001554	87.94	gold quality
pigmented layer of retina	UBERON:0001782	87.74	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-36552	yes	485.27
E-ANND-3	yes	5.90

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFYA, SP1

miRNA regulators (miRDB)

121 targeting ASF1A, 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-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-374A-5P	99.90	71.34	2923

Literature-anchored findings (GeneRIF, showing 40)

• model is proposed in which the synergism between hAsf1 and CAF-1 for nucleosome formation during DNA repair is achieved through a transient physical interaction allowing histone delivery from Asf1 to CAF-1 (PMID:11897662)
• NMR structure of the conserved core of hAsf1 A (PMID:15213445)
• Data suggest that Asf1 provides cells with a buffering system for histone excess generated in response to stalled replication and explains how cells maintain an “active” histone pool available during recovery from replication stresses. (PMID:15664198)
• Evidence of binding between a histone and one of its chaperones and genetic data suggesting that this interaction is important in both the DNA damage response and transcriptional silencing. (PMID:15840725)
• The N- and C-terminal regions of ASF1a and ASF1b determine the different affinities of these two proteins for HIRA, by contacting regions outside the HIRA B domain. CAF-1 p60 also uses B domain-like motifs for binding to ASF1a. (PMID:16980972)
• Studies provide evidence for TLK1B-mediated phosphorylation of Asf1 triggering DNA repair. (PMID:17054786)
• The structure of the conserved domain of human ASF1A in complex with the C-terminal helix of histone H3 using nuclear magnetic resonance spectroscopy was solved. (PMID:17292837)
• the crystal structure, at 2.7 A resolution, of CIA-I in complex with histones H3 and H4 (PMID:17293877)
• the expression of human ASF1A and ASF1B are upregulated followed by cell proliferation signal, but that of ASF1B is uniquely regulated by transcription factors E2F during cell cycle progression (PMID:17328667)
• data link Asf1 chaperone function, histone supply, and replicative unwinding of DNA in chromatin; proposed that Asf1, as a histone acceptor and donor, handles parental and new histones at the replication fork via an Asf1-(H3-H4)-MCM2-7 intermediate (PMID:18096807)
• ASF1A and ASF1B play a role in the efficiency of nucleosome assembly in vivo in human cells. (PMID:18378699)
• IE63 of VZV preferentially bound to ASF1a, and the amino-terminal 30 amino acids of ASF1a were critical for its interaction with IE63. (PMID:18971269)
• Hpc2-related domain of UBN1, UBN2, and Hpc2p is an evolutionarily conserved HIRA/Hir-binding domain, which directly interacts with the N-terminal WD repeats of HIRA/Hir. (PMID:19029251)
• ASF1 cellular levels are tightly controlled by distinct pathways and provide a molecular mechanism for post-translational regulation of dASF1 and hASF1a by TLK kinases. (PMID:20016786)
• Identify marks on histones H3-H4 bound to Asf1 and changes induced upon replication stress. (PMID:20227376)
• HIRA plays a unique, ASF1a-independent role, which is required for the localization of HP1 (PMID:21347226)
• Data show that, like HIRA, UBN1, and ASF1a, CABIN1 is involved in heterochromatinization of the genome of senescent human cells. (PMID:21807893)
• Low ASF1A is associated with familial longevity. (PMID:22247756)
• NHRD domain of UBN1 as being an essential region for HIRA interaction and chromatin organization by the HUCA complex (PMID:22401310)
• The authors propose that Codanin-1 acts as a negative regulator of Asf1 function in chromatin assembly. (PMID:22407294)
• Asf1a plays a role in regulating IE genes by assembling chromatin onto histone-free viral DNA by 3 h postinfection with herpes simplex virus 1 (PMID:22951827)
• Co-depletion of the histone chaperones ASF1a and ASF1b in human cells induces all hallmarks of alternative lengthening of telomeres in both primary and cancer cells. (PMID:24413054)
• Data indicate Tousled-like kinases (TLK1) phosphorylation has an impact on cell cycle proteins Asf1a and Asf1b function. (PMID:24598821)
• The ATR checkpoint pathway causes a histone chaperone normally associated with the replication fork, ASF1a, to degrade through a CRL1(betaTRCP)-dependent ubiquitination/proteasome pathway, leading to the localized dechromatinization and gene repression. (PMID:24700029)
• findings show that ASF1A, a histone-remodeling chaperone specifically enriched in the metaphase II oocyte, is necessary for reprogramming of adult dermal fibroblasts into undifferentiated induced pluripotent stem cell (PMID:25035411)
• Thermodynamic analysis of the quaternary complex together with structural modeling support that ASF1 and MCM2 could form a chaperoning module for histones H3 and H4 protecting them from promiscuous interactions. (PMID:25618846)
• quaternary complex of histone H3-H4 heterodimer with chaperone ASF1 and the replicative helicase subunit MCM2 (PMID:26186914)
• Data show that the ubiquitin-conjugating enzyme E2 RAD6A/B-MDM2 ubiquitin ligase machinery regulates anti-silencing function 1A protein (ASF1A) degradation. (PMID:26336826)
• These data suggest that CAF-1- and ASF1A-H3-H4-dependent deposition of the histone (H3-H4)2 tetramers is compatible with MMR and protects the discontinuous daughter strand from unnecessary degradation by MMR machinery. (PMID:26945061)
• ASF1A is aberrantly over-expressed in GIC tumors and plays key roles in GIC development and progression by stimulating the transcription of beta-catenin target genes. (PMID:28625518)
• ASF1a promotes non-homologous end joining repair by facilitating phosphorylation of MDC1 by ATM at double-strand breaks. (PMID:28943310)
• uncovered DNA-PKcs-dependent DNA damage-induced ASF1A phosphorylation, which enhances chromatin assembly, promoting MMS22L-TONSL recruitment and, hence, Rad51 loading. (PMID:29478807)
• ASF1A depletion leads to increased recruitment of DNA-PKcs to DSBs. (PMID:29954236)
• faithful transmission of histone variants involves ASF1 and can be impacted by replication stress, with ensuing consequences for cell fate and tumorigenesis (PMID:30093638)
• We demonstrate that the CIA-targeting complex promotes the ability of FBXL5 to degrade iron regulatory proteins. In addition, the FBXL5-CIA-targeting complex interaction is regulated by oxygen (O2) tension displaying a robust association in 21% O2 that is severely diminished in 1% O2 and contributes to O2-dependent regulation of IRP degradation (PMID:31229404)
• ASF1A regulated H4(Y72ph) and promotes autophagy in colon cancer cells via a kinase activity through regulation of ATG (PMID:31286799)
• In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma. (PMID:31744829)
• Chk1 promotes non-homologous end joining in G1 through direct phosphorylation of ASF1A. (PMID:33503415)
• Elevated expression of ASF1B correlates with poor prognosis in human lung adenocarcinoma. (PMID:33576264)
• Tousled-like kinase 2 targets ASF1 histone chaperones through client mimicry. (PMID:35136069)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Asf1a	ENSMUSG00000019857
rattus_norvegicus	Asf1a	ENSRNOG00000000415
drosophila_melanogaster	asf1	FBGN0029094
caenorhabditis_elegans		WBGENE00006817
caenorhabditis_elegans	asfl-1	WBGENE00007277

Paralogs (1): ASF1B (ENSG00000105011)

Protein

Protein identifiers

Histone chaperone ASF1A — Q9Y294 (reviewed: Q9Y294)

Alternative names: Anti-silencing function protein 1 homolog A, CCG1-interacting factor A

All UniProt accessions (1): Q9Y294

UniProt curated annotations — full annotation on UniProt →

Function. Histone chaperone that facilitates histone deposition and histone exchange and removal during nucleosome assembly and disassembly. Cooperates with chromatin assembly factor 1 (CAF-1) to promote replication-dependent chromatin assembly and with HIRA to promote replication-independent chromatin assembly. Promotes homologous recombination-mediated repair of double-strand breaks (DSBs) at stalled or collapsed replication forks: acts by mediating histone replacement at DSBs, leading to recruitment of the MMS22L-TONSL complex and subsequent loading of RAD51. Also involved in the nuclear import of the histone H3-H4 dimer together with importin-4 (IPO4): specifically recognizes and binds newly synthesized histones with the monomethylation of H3 ‘Lys-9’ and acetylation at ‘Lys-14’ (H3K9me1K14ac) marks, and diacetylation at ‘Lys-5’ and ‘Lys-12’ of H4 (H4K5K12ac) marks in the cytosol. Required for the formation of senescence-associated heterochromatin foci (SAHF) and efficient senescence-associated cell cycle exit.

Subunit / interactions. Interacts with histone H3 (via C-terminus), including histone H3.1, H3.2 and H3.3, and histone H4; the interaction with H3 is direct. Probably interacts with the heterodimeric form of H3-H4 taking the place of the second dimer. Interacts with the CHAF1A, CHAF1B and RBBP4 subunits of the CAF-1 complex. Interacts with CABIN1, HAT1, HIRA, NASP, TAF1 and UBN1. Found in a soluble complex with NASP and histones H3 and H4; the interaction with NASP is probably indirect and mediated by H3-H4. Interacts with CDAN1. Found in a cytosolic complex with IPO4 and histones H3 and H4. Interacts with CREBBP.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Ubiquitously expressed.

Post-translational modifications. Phosphorylated by TLK1 and TLK2. Highly phosphorylated in S-phase and at lower levels in M-phase. TLK2-mediated phosphorylation at Ser-192 prevents proteasome-dependent degradation. Phosphorylation at Ser-192 by PRKDC in response to DNA damage promotes the histone chaperone activity and ability to replace histones at double-strand breaks (DSBs) at stalled or collapsed replication forks, leading to RAD51 recruitment.

Similarity. Belongs to the ASF1 family.

RefSeq proteins (1): NP_054753* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006818	ASF1-like	Family
IPR036747	ASF1-like_sf	Homologous_superfamily

Pfam: PF04729

UniProt features (35 total): mutagenesis site 12, strand 11, helix 5, region of interest 2, sequence conflict 2, chain 1, short sequence motif 1, modified residue 1

Structure

Experimental structures (PDB)

20 structures.

PDB	Method	Resolution (Å)
6ZUF	X-RAY DIFFRACTION	1.8
6F0H	X-RAY DIFFRACTION	1.98
6F0F	X-RAY DIFFRACTION	2
7LNY	X-RAY DIFFRACTION	2.1
8CJ2	X-RAY DIFFRACTION	2.13
6F0G	X-RAY DIFFRACTION	2.3
8CJ1	X-RAY DIFFRACTION	2.56
2I32	X-RAY DIFFRACTION	2.7
2IO5	X-RAY DIFFRACTION	2.7
7LO0	X-RAY DIFFRACTION	2.71
8Z50	X-RAY DIFFRACTION	2.8
8BV1	X-RAY DIFFRACTION	2.83
7V6Q	X-RAY DIFFRACTION	3
8CJ3	X-RAY DIFFRACTION	3
3AAD	X-RAY DIFFRACTION	3.3
5C3I	X-RAY DIFFRACTION	3.5
9CVC	ELECTRON MICROSCOPY	3.5
9IMZ	ELECTRON MICROSCOPY	3.75
1TEY	SOLUTION NMR
2IIJ	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y294-F1	84.86	0.75

Functional residue map

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

Post-translational modifications (1): 192

Mutagenesis-validated functional residues (12):

Position	Phenotype
88	loss of interaction with tlk2. reduced phosphorylation.
94	abrogates interaction with histone h3 and histone h4. loss of interaction with tlk2. reduced phosphorylation.
108	reduces interaction with histone h3.
166	does not affect phosphorylation in response to dna damage.
175	does not affect phosphorylation in response to dna damage.
192	abolished phosphorylation in response to dna damage.
192	mimics phosphorylation; promoting recruitment to chromatin in response to dna damage.
36–37	abrogates interaction with hira and induction of senescence-associated heterochromatin foci.
37	abrogates interaction with chaf1b and hira.
49	loss of interaction with tlk2.
54	reduces interaction with histone h3.
62–64	abrogates interaction with hira and induction of senescence-associated heterochromatin foci.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-2559584	Formation of Senescence-Associated Heterochromatin Foci (SAHF)
R-HSA-2262752	Cellular responses to stress
R-HSA-2559583	Cellular Senescence
R-HSA-2559586	DNA Damage/Telomere Stress Induced Senescence
R-HSA-8953897	Cellular responses to stimuli

MSigDB gene sets: 264 (showing top): GOBP_DNA_TEMPLATED_DNA_REPLICATION_MAINTENANCE_OF_FIDELITY, HORIUCHI_WTAP_TARGETS_DN, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, TGCACTT_MIR519C_MIR519B_MIR519A, MATTIOLI_MGUS_VS_PCL, GOBP_OSTEOBLAST_DIFFERENTIATION, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, ATGTTAA_MIR302C, PUJANA_CHEK2_PCC_NETWORK, GOBP_NUCLEAR_TRANSPORT, GTGCCTT_MIR506, ONKEN_UVEAL_MELANOMA_UP, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, WTGAAAT_UNKNOWN, GNF2_CDC2

GO Biological Process (11): osteoblast differentiation (GO:0001649), DNA repair (GO:0006281), nucleosome assembly (GO:0006334), DNA replication-dependent chromatin assembly (GO:0006335), replication fork processing (GO:0031297), muscle cell differentiation (GO:0042692), DNA repair-dependent chromatin remodeling (GO:0140861), double-strand break repair via homologous recombination (GO:0000724), chromatin organization (GO:0006325), DNA damage response (GO:0006974), protein localization to chromatin (GO:0071168)

GO Molecular Function (4): chromatin binding (GO:0003682), histone binding (GO:0042393), histone chaperone activity (GO:0140713), protein binding (GO:0005515)

GO Cellular Component (6): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), protein-containing complex (GO:0032991), site of double-strand break (GO:0035861), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
DNA Damage/Telomere Stress Induced Senescence	1
Cellular responses to stimuli	1
Cellular responses to stress	1
Cellular Senescence	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell differentiation	2
DNA damage response	2
chromatin organization	2
binding	2
cellular anatomical structure	2
ossification	1
DNA metabolic process	1
nucleosome organization	1
protein-DNA complex assembly	1
DNA-templated DNA replication maintenance of fidelity	1
muscle structure development	1
chromatin remodeling	1
recombinational repair	1
double-strand break repair	1
cellular component organization	1
cellular response to stress	1
protein localization to chromosome	1
protein binding	1
histone binding	1
protein carrier activity	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular_component	1
site of DNA damage	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

2948 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ASF1A	UBN1	Q9NPG3	986
ASF1A	CABIN1	Q9Y6J0	973
ASF1A	H3C1	P02295	958
ASF1A	H3-3A	P06351	936
ASF1A	H3-4	Q16695	926
ASF1A	H3-7	Q5TEC6	926
ASF1A	H3-5	Q6NXT2	926
ASF1A	H3C14	Q71DI3	926
ASF1A	SRSF1	Q07955	889
ASF1A	HIRA	P54198	880
ASF1A	TLK1	Q9UKI8	842
ASF1A	TLK2	Q86UE8	836
ASF1A	NASP	P49321	833
ASF1A	CHAF1B	Q13112	803
ASF1A	IPO4	Q8TEX9	797

IntAct

136 interactions, top by confidence:

A	B	Type	Score
ASF1A	H4C16	psi-mi:“MI:0915”(physical association)	0.950
H4C16	ASF1A	psi-mi:“MI:0915”(physical association)	0.950
ASF1A	H4C16	psi-mi:“MI:0914”(association)	0.950
HIRA	ASF1A	psi-mi:“MI:0915”(physical association)	0.900
ASF1A	HIRA	psi-mi:“MI:0914”(association)	0.900
HIRA	ASF1A	psi-mi:“MI:0407”(direct interaction)	0.900
ASF1A	MCM2	psi-mi:“MI:0915”(physical association)	0.890
ASF1A	MCM2	psi-mi:“MI:0914”(association)	0.890
MCM2	ASF1A	psi-mi:“MI:0915”(physical association)	0.890
TLK2	DYNLL1	psi-mi:“MI:0914”(association)	0.890
RBBP7	CDK2AP1	psi-mi:“MI:0914”(association)	0.840
MCM2	MCM4	psi-mi:“MI:0914”(association)	0.830
HAT1	RBBP4	psi-mi:“MI:0914”(association)	0.800
CDAN1	ASF1B	psi-mi:“MI:0914”(association)	0.800
RBBP4	CDK2AP1	psi-mi:“MI:0914”(association)	0.790

BioGRID (456): ASF1A (Two-hybrid), PRR3 (Two-hybrid), ASF1A (Two-hybrid), ASF1A (Two-hybrid), ASF1A (Proximity Label-MS), CENPB (Affinity Capture-MS), COPB1 (Affinity Capture-MS), NASP (Affinity Capture-MS), PPP1CA (Affinity Capture-MS), PPP1CB (Affinity Capture-MS), RBBP4 (Affinity Capture-MS), RBBP7 (Affinity Capture-MS), SPTBN2 (Affinity Capture-MS), HIRA (Affinity Capture-MS), HAT1 (Affinity Capture-MS)

ESM2 similar proteins: A6NIH7, B9G4M9, G5EC37, G5EDM7, O04064, O04407, O10335, O19177, P0CM27, P15130, P22484, P23915, P24872, P33802, P55082, P60571, P68327, Q02645, Q10658, Q11107, Q13432, Q17297, Q17603, Q17QJ0, Q19326, Q1E0W9, Q2KIG1, Q3C1E9, Q3SYR2, Q5R9E4, Q62885, Q66JA9, Q6DIP1, Q6DLD9, Q6IMP4, Q6INE2, Q6NYY4, Q6UDF4, Q75CM4, Q75D88

Diamond homologs: O74515, P0CM26, P0CM27, P32447, Q17603, Q17QJ0, Q19326, Q1E0W9, Q2GQS2, Q2KIG1, Q2UKV7, Q3C1E9, Q4IR08, Q4PBU8, Q4WXX5, Q54N45, Q59MV1, Q5B3I9, Q69DB9, Q6BYE5, Q6CI62, Q6CN69, Q6DIP1, Q6FL84, Q6NY34, Q6NYY4, Q759F6, Q7S1X9, Q7T0M6, Q8SRM1, Q9C9M6, Q9CQE6, Q9DAP7, Q9LS09, Q9NVP2, Q9V464, Q9Y294

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
TLK2	“up-regulates quantity by stabilization”	ASF1A	phosphorylation
CHEK1	“up-regulates activity”	ASF1A	phosphorylation
ASF1A	“up-regulates activity”	MDC1	binding
MDM2	“down-regulates quantity by destabilization”	ASF1A	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 75 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
PRC2 methylates histones and DNA	7	23.2×	7e-06
NuRD complex assembly	7	21.4×	7e-06
Defective pyroptosis	6	20.4×	4e-05
ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression	6	19.9×	4e-05
Interaction of NuRD complexes with transcription factors	7	19.3×	9e-06
Deposition of new CENPA-containing nucleosomes at the centromere	5	17.2×	3e-04
Regulation of endogenous retroelements by KRAB-ZFP proteins	7	16.2×	2e-05
Negative Regulation of CDH1 Gene Transcription	6	15.7×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
nucleosome assembly	15	30.5×	5e-16
DNA replication	8	19.2×	1e-06
chromatin organization	8	11.5×	5e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	3
Uncertain significance	18
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
148658	GRCh38/hg38 6q22.1-22.32(chr6:117607147-126699980)x3	Pathogenic
1527278	GRCh37/hg19 6q22.1-22.31(chr6:116212698-119482708)	Pathogenic
180227	NC_000006.11:g.(116681080_116735056)_(119687719_119775014)del	Pathogenic
2427242	NC_000006.11:g.(?116441236)(119252888_?)del	Pathogenic
4682663	GRCh37/hg19 6q22.1-22.33(chr6:114742335-127346798)x1	Pathogenic
978186	NC_000006.11:g.116734559_123648104del	Pathogenic
1341103	GRCh37/hg19 6q22.1-22.31(chr6:117441803-123349672)x3	Likely pathogenic
151218	GRCh38/hg38 6q22.1-22.31(chr6:116815199-119718887)x1	Likely pathogenic
2574685	GRCh37/hg19 6q21-22.31(chr6:112713854-124105184)	Likely pathogenic

SpliceAI

534 predictions. Top by Δscore:

Variant	Effect	Δscore
6:118900877:TTCAG:T	donor_loss	1.0000
6:118900878:TCAG:T	donor_loss	1.0000
6:118900879:CAG:C	donor_loss	1.0000
6:118900880:AGGTA:A	donor_loss	1.0000
6:118900881:GG:G	donor_loss	1.0000
6:118900882:GTAA:G	donor_loss	1.0000
6:118900883:T:A	donor_loss	1.0000
6:118905640:A:AG	acceptor_gain	1.0000
6:118905641:A:G	acceptor_gain	1.0000
6:118905647:TCTA:T	acceptor_loss	1.0000
6:118905649:TA:T	acceptor_loss	1.0000
6:118905650:A:AT	acceptor_loss	1.0000
6:118905651:GGCT:G	acceptor_gain	1.0000
6:118905824:CTAAG:C	donor_loss	1.0000
6:118905827:AGG:A	donor_loss	1.0000
6:118905828:GGT:G	donor_loss	1.0000
6:118905829:G:C	donor_loss	1.0000
6:118905830:T:A	donor_loss	1.0000
6:118907397:TCTA:T	acceptor_loss	1.0000
6:118907400:A:AG	acceptor_gain	1.0000
6:118907401:G:GG	acceptor_gain	1.0000
6:118907401:GC:G	acceptor_gain	1.0000
6:118907401:GCT:G	acceptor_gain	1.0000
6:118907401:GCTT:G	acceptor_gain	1.0000
6:118907401:GCTTC:G	acceptor_gain	1.0000
6:118894520:AAGGT:A	donor_loss	0.9900
6:118894523:G:GA	donor_loss	0.9900
6:118894524:T:G	donor_loss	0.9900
6:118900764:A:AG	acceptor_gain	0.9900
6:118900765:G:GA	acceptor_gain	0.9900

AlphaMissense

1340 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:118894424:T:A	V4D	1.000
6:118894445:T:A	V11E	1.000
6:118894448:T:C	L12P	1.000
6:118894455:C:A	N14K	1.000
6:118894455:C:G	N14K	1.000
6:118894478:T:C	F22S	1.000
6:118894483:T:C	F24L	1.000
6:118894484:T:C	F24S	1.000
6:118894485:C:A	F24L	1.000
6:118894485:C:G	F24L	1.000
6:118894490:T:A	I26N	1.000
6:118894490:T:C	I26T	1.000
6:118894490:T:G	I26S	1.000
6:118894495:T:C	F28L	1.000
6:118894496:T:C	F28S	1.000
6:118894497:C:A	F28L	1.000
6:118894497:C:G	F28L	1.000
6:118894501:T:C	C30R	1.000
6:118894502:G:A	C30Y	1.000
6:118894503:C:G	C30W	1.000
6:118894514:T:C	L34P	1.000
6:118900769:T:C	L38S	1.000
6:118900769:T:G	L38W	1.000
6:118900774:T:A	W40R	1.000
6:118900774:T:C	W40R	1.000
6:118900775:G:C	W40S	1.000
6:118900776:G:C	W40C	1.000
6:118900776:G:T	W40C	1.000
6:118900786:T:A	Y44N	1.000
6:118900786:T:C	Y44H	1.000

dbSNP variants (sampled 300 via entrez): RS1000068399 (6:118901193 A>G), RS1000081099 (6:118894852 C>T), RS1000104029 (6:118894157 T>G), RS1000202408 (6:118909486 GT>G,GTT), RS1000266195 (6:118905927 A>G,T), RS1000907775 (6:118908556 T>C), RS1001006469 (6:118902384 AACT>A), RS1001236836 (6:118908299 A>G), RS1001403027 (6:118905660 A>G), RS1001444496 (6:118898955 A>C), RS1001487821 (6:118895918 TATTC>T), RS1001809130 (6:118894126 G>A,T), RS1001908081 (6:118905203 A>C,G), RS1002152051 (6:118893929 G>A,C), RS1002167019 (6:118899263 C>G,T)

Disease associations

OMIM: gene MIM:609189 | disease phenotypes: MIM:617082

GenCC curated gene-disease

Mondo (4): intellectual disability (MONDO:0001071), microcephaly (MONDO:0001149), congenital disorder of glycosylation, type IAA (MONDO:0014904), 6q terminal deletion syndrome (MONDO:0019164)

Orphanet (2): 6q terminal deletion syndrome (Orphanet:75857), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000252	Microcephaly

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000363_13	QT interval	5.000000e-22
GCST009597_112	Multiple sclerosis	3.000000e-10
GCST90002395_486	Mean platelet volume	2.000000e-17

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004682	QT interval

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3392950 (SINGLE PROTEIN)

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 20 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.22	IC50	600	nM	CHEMBL199405
5.52	IC50	3000	nM	CHEMBL3394920
5.00	IC50	1e+04	nM	CHEMBL3394913

PubChem BioAssay actives

3 with measured affinity, of 46 total; 3 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-[(E)-(5-bromo-2-hydroxyphenyl)methylideneamino]pyridine-4-carboxamide	1190530: Inhibition of His-tagged human Asf1a binding with H3/H4 assessed as fluorescence intensity after 30 mins by ALPHA assay	ic50	0.6000	uM
4-acetamido-N-[(E)-(5-bromo-2-hydroxyphenyl)methylideneamino]benzamide	1190530: Inhibition of His-tagged human Asf1a binding with H3/H4 assessed as fluorescence intensity after 30 mins by ALPHA assay	ic50	3.0000	uM
4-benzamido-N-[(E)-[3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]methylideneamino]benzamide	1190530: Inhibition of His-tagged human Asf1a binding with H3/H4 assessed as fluorescence intensity after 30 mins by ALPHA assay	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression	4
bisphenol A	affects expression, affects cotreatment, decreases methylation, decreases expression, increases methylation	3
Tobacco Smoke Pollution	increases expression	3
Valproic Acid	affects expression, increases expression	3
potassium chromate(VI)	decreases expression, affects cotreatment	2
mercuric bromide	increases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cadmium Chloride	increases abundance, increases expression, decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
FR900359	increases phosphorylation	1
dicrotophos	decreases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
bis(tri-n-butyltin)oxide	increases expression	1
lead acetate	decreases expression, affects cotreatment	1
1,2-diamino-4-nitrobenzene	increases expression	1
cresidine	increases expression	1
methylparaben	decreases expression	1
sulforaphane	increases expression	1
zinc protoporphyrin	affects cotreatment, decreases expression	1
sodium arsenite	affects cotreatment, increases abundance, increases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
2-amino-3-methylimidazo(4,5-f)quinoline	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
ethyl acrylate	increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3395841	Binding	Inhibition of globular core domain of Asf1 (unknown origin) binding with H3/H4 after 15 to 30 mins by ELISA assay	Development of novel Asf1-H3/H4 inhibitors. — Bioorg Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_XL58	HAP1 ASF1A (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders