CCAR2

Summary

CCAR2 (cell cycle and apoptosis regulator 2, HGNC:23360) is a protein-coding gene on chromosome 8p21.3, encoding Cell cycle and apoptosis regulator protein 2 (Q8N163). Core component of the DBIRD complex, a multiprotein complex that acts at the interface between core mRNP particles and RNA polymerase II (RNAPII) and integrates transcript elongation with the regulation of alternative splicing: the DBIRD complex affects local transcript elongati….

Enables RNA polymerase II complex binding activity and enzyme inhibitor activity. Involved in several processes, including mitochondrial fragmentation involved in apoptotic process; regulation of primary metabolic process; and regulation of signal transduction. Located in several cellular components, including mitochondrial matrix; nucleoplasm; and spindle. Part of DBIRD complex.

Source: NCBI Gene 57805 — RefSeq curated summary.

At a glance

• GWAS associations: 16
• Clinical variants (ClinVar): 179 total — 1 likely-pathogenic
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001393997

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23360
Approved symbol	CCAR2
Name	cell cycle and apoptosis regulator 2
Location	8p21.3
Locus type	gene with protein product
Status	Approved
Aliases	DBC-1, DBC1, NET35
Ensembl gene	ENSG00000158941
Ensembl biotype	protein_coding
OMIM	607359
Entrez	57805

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 26 protein_coding, 3 retained_intron

ENST00000308511, ENST00000389279, ENST00000518989, ENST00000520536, ENST00000520738, ENST00000520861, ENST00000521020, ENST00000521301, ENST00000521436, ENST00000521837, ENST00000522599, ENST00000523349, ENST00000523801, ENST00000910071, ENST00000910072, ENST00000910073, ENST00000910074, ENST00000910075, ENST00000910076, ENST00000910077, ENST00000910078, ENST00000910079, ENST00000910080, ENST00000939462, ENST00000939463, ENST00000939464, ENST00000939465, ENST00000939466, ENST00000952221

RefSeq mRNA: 4 — MANE Select: NM_001393997 NM_001363068, NM_001363069, NM_001393997, NM_021174

CCDS: CCDS34863

Canonical transcript exons

ENST00000308511 — 21 exons

Exon	Start	End
ENSE00000980114	22617696	22617778
ENSE00001159508	22617420	22617564
ENSE00001279614	22616012	22616248
ENSE00001293586	22614838	22615001
ENSE00001307323	22606910	22607024
ENSE00001326732	22606607	22606698
ENSE00001350705	22606085	22606176
ENSE00001404429	22605736	22605831
ENSE00001505332	22615682	22615912
ENSE00002112591	22604757	22604842
ENSE00002137122	22619638	22620471
ENSE00003544782	22614092	22614314
ENSE00003574055	22618349	22618495
ENSE00003599599	22607969	22608065
ENSE00003624306	22618617	22618728
ENSE00003634836	22619150	22619355
ENSE00003641568	22614390	22614503
ENSE00003643139	22618827	22619015
ENSE00003677279	22613017	22613136
ENSE00003786141	22615425	22615596
ENSE00003789868	22607196	22607325

Expression profiles

Bgee: expression breadth ubiquitous, 252 present calls, max score 98.37.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 49.6110 / max 288.1639, expressed in 1818 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
87837	43.5871	1814
87838	5.8763	1656
87839	0.1476	61

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	98.37	gold quality
ventricular zone	UBERON:0003053	98.24	gold quality
ganglionic eminence	UBERON:0004023	98.22	gold quality
right uterine tube	UBERON:0001302	97.74	gold quality
right testis	UBERON:0004534	97.48	gold quality
left testis	UBERON:0004533	97.38	gold quality
granulocyte	CL:0000094	97.31	gold quality
skin of leg	UBERON:0001511	97.22	gold quality
cerebellar hemisphere	UBERON:0002245	97.17	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.14	gold quality
vermiform appendix	UBERON:0001154	97.13	gold quality
cerebellar cortex	UBERON:0002129	97.08	gold quality
stromal cell of endometrium	CL:0002255	97.07	gold quality
right ovary	UBERON:0002118	97.07	gold quality
body of uterus	UBERON:0009853	97.00	gold quality
sural nerve	UBERON:0015488	96.92	gold quality
left ovary	UBERON:0002119	96.85	gold quality
left uterine tube	UBERON:0001303	96.80	gold quality
skin of abdomen	UBERON:0001416	96.79	gold quality
prefrontal cortex	UBERON:0000451	96.78	gold quality
adenohypophysis	UBERON:0002196	96.77	gold quality
right adrenal gland cortex	UBERON:0035827	96.71	gold quality
tibial nerve	UBERON:0001323	96.70	gold quality
gall bladder	UBERON:0002110	96.70	gold quality
metanephros cortex	UBERON:0010533	96.68	gold quality
right lobe of thyroid gland	UBERON:0001119	96.65	gold quality
right adrenal gland	UBERON:0001233	96.65	gold quality
left adrenal gland cortex	UBERON:0035825	96.65	gold quality
left adrenal gland	UBERON:0001234	96.62	gold quality
right frontal lobe	UBERON:0002810	96.58	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.29
E-MTAB-9543	no	2.38

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, ESR1, ESR2, SIRT1, TP53

miRNA regulators (miRDB)

51 targeting CCAR2, 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-3613-3P	100.00	76.36	7965
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-29B-2-5P	99.67	68.98	1726
HSA-MIR-4663	99.62	65.33	957
HSA-MIR-3128	99.50	67.85	1258
HSA-MIR-3182	99.40	68.15	2454
HSA-MIR-12113	99.32	67.54	1072
HSA-MIR-133A-5P	99.28	69.13	941
HSA-MIR-3978	99.24	68.39	2201
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-4478	99.07	65.16	2320
HSA-MIR-140-3P	99.04	67.69	1324
HSA-MIR-29B-1-5P	98.86	68.35	1364
HSA-MIR-4539	98.78	67.18	888
HSA-MIR-583	98.71	67.44	1791
HSA-MIR-31-5P	98.58	68.35	1239
HSA-MIR-299-5P	98.56	71.14	1140
HSA-MIR-138-5P	98.43	70.49	1292

Literature-anchored findings (GeneRIF, showing 40)

• Caspase-dependent processing of DBC-1 may act as a feed-forward mechanism to promote apoptosis and possibly also tumor suppression. (PMID:15824730)
• DBC-1 functions to modulate ER alpha expression and hormone-independent breast cancer cell survival. (PMID:17473282)
• biological function for DBC-1 in the modulation of ERalpha expression and hormone-independent breast cancer cell survival (PMID:17473282)
• DBC1 directly interacts with SIRT1 and inhibits SIRT1 activity in vitro and in vivo (PMID:18235501)
• DBC1 (deleted in breast cancer 1) acts as a native inhibitor of SIRT1 in human cells (PMID:18235502)
• DBC1 and its homologs are likely to regulate the activity of SIRT1 or related deacetylases by sensing the soluble products or substrates of the NAD-dependent deacetylation reaction. (PMID:18418069)
• Expression of DBC1 also enhanced the binding of AR to chromatinized template in vivo, whereas knockdown of DBC1 impaired the binding of AR to endogenous prostate-specific antigen (PSA) gene in the prostate cancer (PMID:19126541)
• The identified components revealed factors involved in histone methylation and cell cycle control and include Ash2L, RbBP5, WDR5, HCF-1, DBC-1, and EMSY. (PMID:19131338)
• Results identify DBC1 as a novel cellular inhibitor of SUV39H1 activity, and suggest that DBC1 may be an important regulator of heterochromatin formation and genomic stability by disrupting the SUV39H1-SirT1 complex and inactivating both enzymes. (PMID:19218236)
• Expression of DBC1 and SIRT1 is a significant prognostic indicator for gastric carcinoma patients. (PMID:19509139)
• [review] summarizes the current understandings on p30 DBC functions, with a focus on the proposed roles of p30 DBC in tumorigenesis (PMID:19657230)
• New role for DBC1 as an in vivo regulator of SIRT1 activity and liver steatosis, in which interaction with SIRT1 may serve as a new target for therapies aimed at nonalcoholic liver steatosis. (PMID:20071779)
• results implicate the principal role of DBC1 in regulating ERbeta-dependent gene expressions (PMID:20074560)
• DBC1 may modulate the cellular functions of BRCA1 and have important implications in the understanding of carcinogenesis in breast tissue. (PMID:20160719)
• HDAC3 is negatively regulated by the nuclear protein DBC1 (PMID:21030595)
• Suggest that DBC1 may promote tumor progression, and DBC1 could be a prognostic biomarker in esophageal squamous cell carcinoma. (PMID:22127596)
• data indicate that the DBIRD complex (consisting of DBC1 and ZNF326) acts at the interface between mRNP particles and RNAPII, integrating transcript elongation with the regulation of alternative splicing (PMID:22446626)
• Data indicate that an increase in cAMP/PKA activity resulted in the dissociation of SIRT1 and DBC1 in an AMP-activated protein kinase (AMPK)-dependent manner. (PMID:22553202)
• DBC1 phosphorylation by ATM/ATR inhibits SIRT1 deacetylase in response to DNA damage. (PMID:22735644)
• These results suggest that DBC1 is over-expressed in colorectal cancer and that it might serve as a predictor for selecting patients at high risk of poor prognosis. (PMID:23299276)
• DBC1 enhances cell survival against UV irradiation.Therefore, DBC1 plays a critical role in maintaining genomic stability and cellular integrity following UV-induced genotoxic stress. (PMID:23352644)
• DBC1 is an important co-factor for the control of the IKK-beta-NF-kappaB signaling pathway that regulates anoikis. (PMID:23588592)
• DBC1 may be implicated in the regulation of cancer cell energy metabolism. [Review] (PMID:23841676)
• Protein acetylation serves as an endogenous regulatory mechanism for SIRT1-DBC1 binding. (PMID:23892437)
• This study demonstrates that the acetylation status of P53 and the expression of SIRT1, DBC1, and AR could be new prognostic indicators for clear cell renal cell carcinoma (PMID:24018803)
• demonstrates that SIRT1- and DBC1-related pathways may be involved in the progression of soft-tissue sarcomas and can be used as clinically significant prognostic indicators for sarcoma patients (PMID:24019980)
• MOF acetylation of DBC1 inhibits binding to SirT1 and serves as a mechanism that connects DNA damage signaling to SirT1 and cell fate determination. (PMID:24126058)
• Our findings integrate KSR1 into a network involving DBC1 and SIRT1, which results in the regulation of p53 acetylation and its transcriptional activity. (PMID:24129246)
• Results reveal novel mechanisms by which TFII-I and DBC1 can modulate cellular fate by affecting cell-cycle control as well as the homologous recombination pathway. (PMID:24231951)
• DBC1 as a novel regulator of gluconeogenesis. (PMID:24415752)
• cytoplasmic MCC-DBC1 interaction sequesters DBC1 away from the nucleus, thereby removing a brake on DBC1 nuclear targets, such as SIRT1 (PMID:24824780)
• CK2 alpha is an independent prognostic indicator for gastric carcinoma patients and is involved in tumorigenesis by regulating the phosphorylation of DBC1. (PMID:24962073)
• We propose that DBC1 is part of the molecular machinery that regulates fat storage capacity in adipocytes and participates in the “turn-off” switch that limits adipocyte fat accumulation. (PMID:25053585)
• The results link Chk2 and REGgamma to the mechanism underlying the DBC1-dependent SIRT1 inhibition. (PMID:25361978)
• DBC1 modification by Small Ubiquitin-like Modifier 2/3 is crucial for p53 transactivation under genotoxic stress. (PMID:25406032)
• molecular mechanism underlying DBC1 function in PEA3-mediated transcription involves inhibition of SIRT1 interaction with PEA3 and of SIRT1-mediated deacetylation of PEA3 (PMID:25417701)
• this study provides insight into the structure and evolution of DBC1 and CCAR1, which may impact future studies on the biological functions of these proteins. (PMID:25610865)
• Although DBC1 gene expression was reduced in adipose tissue from obese subjects, it was negatively associated with ADIPOQ gene expression in VAT, suggesting that DBC1 might promote visceral adipose tissue dysfunction. (PMID:25648830)
• These results clearly indicate a novel mechanism in which CCAR2 may regulate the transcriptional activation function of LXRalpha due to its specific inhibition of SIRT1 and serve to regulate cellular proliferation. (PMID:25661920)
• DBC1 might promote adipose tissue inflammation and senescence in obese subjects (PMID:25682741)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ccar2	ENSDARG00000038302
mus_musculus	Ccar2	ENSMUSG00000033712
rattus_norvegicus	Ccar2	ENSRNOG00000018295
caenorhabditis_elegans		WBGENE00003085

Paralogs (1): CCAR1 (ENSG00000060339)

Protein

Protein identifiers

Cell cycle and apoptosis regulator protein 2 — Q8N163 (reviewed: Q8N163)

Alternative names: Cell division cycle and apoptosis regulator protein 2, DBIRD complex subunit KIAA1967, Deleted in breast cancer gene 1 protein, NET35, p30 DBC

All UniProt accessions (9): Q8N163, E5RFJ3, E5RGU7, E5RHH8, E5RHJ4, G3V119, H0YB24, H0YC58, H0YC69

UniProt curated annotations — full annotation on UniProt →

Function. Core component of the DBIRD complex, a multiprotein complex that acts at the interface between core mRNP particles and RNA polymerase II (RNAPII) and integrates transcript elongation with the regulation of alternative splicing: the DBIRD complex affects local transcript elongation rates and alternative splicing of a large set of exons embedded in (A + T)-rich DNA regions. Inhibits SIRT1 deacetylase activity leading to increasing levels of p53/TP53 acetylation and p53-mediated apoptosis. Inhibits SUV39H1 methyltransferase activity. Mediates ligand-dependent transcriptional activation by nuclear hormone receptors. Plays a critical role in maintaining genomic stability and cellular integrity following UV-induced genotoxic stress. Regulates the circadian expression of the core clock components NR1D1 and BMAL1. Enhances the transcriptional repressor activity of NR1D1 through stabilization of NR1D1 protein levels by preventing its ubiquitination and subsequent degradation. Represses the ligand-dependent transcriptional activation function of ESR2. Acts as a regulator of PCK1 expression and gluconeogenesis by a mechanism that involves, at least in part, both NR1D1 and SIRT1. Negatively regulates the deacetylase activity of HDAC3 and can alter its subcellular localization. Positively regulates the beta-catenin pathway (canonical Wnt signaling pathway) and is required for MCC-mediated repression of the beta-catenin pathway. Represses ligand-dependent transcriptional activation function of NR1H2 and NR1H3 and inhibits the interaction of SIRT1 with NR1H3. Plays an important role in tumor suppression through p53/TP53 regulation; stabilizes p53/TP53 by affecting its interaction with ubiquitin ligase MDM2. Represses the transcriptional activator activity of BRCA1. Inhibits SIRT1 in a CHEK2 and PSEM3-dependent manner and inhibits the activity of CHEK2 in vitro.

Subunit / interactions. Component of the DBIRD complex. Interacts with ZNF326/ZIRD; the interaction is direct. Interacts (via N-terminus) with SIRT1, which inhibits the deacetylation of substrates. Interacts (via N-terminus) with SUV39H1; this interaction abolishes the interaction with SIRT1. Component of a nuclear receptor-mediated transcription complex composed of at least ZNF335, CCAR2 and EMSY; the complex stimulates the transcription of nuclear receptor target genes such as SOX9 and HOXA1. Within the complex interacts with EMSY and interacts with ZNF335 (via C-terminus). Components of this complex may associate with components of a histone methylation complex to form a complex at least composed of ZNF335, HCFC1, CCAR2, EMSY, MKI67, RBBP5, ASH2L and WDR5. Within this complex, interacts with ASH2L. Interacts with NR1D1. Interacts (via N-terminus) with ESR1 and ESR2. Interacts (via N-terminus) with HDAC3 (via C-terminus). Interacts with HDAC1 and MED2F. Interacts with MCC. Interacts (via N-terminus) with NR1H2 and NR1H3 in a ligand-independent manner. Interacts with CSNK2A1. Interacts (via N-terminus) with p53/TP53. Interacts (via N-terminus) with BRCA1 (via the BRCT domains). Interacts (via N-terminus) with CHEK2 (via protein kinase domain). Interacts with PSEM3. Interacts (via N-terminus) with PSIA3 and SENP1. The sumoylated form shows a preferential interaction with SIRT1 as compared to its unmodified form. Interacts with CECR2; may form part of the CERF-1 and/or CEF-5 ISWI chromatin remodeling complexes in embryonic stem cells.

Subcellular location. Nucleus. Cytoplasm. Cytoskeleton. Spindle.

Tissue specificity. Expressed in gastric carcinoma tissue and the expression gradually increases with the progression of the carcinoma (at protein level). Expressed ubiquitously in normal tissues. Expressed in 84 to 100% of neoplastic breast, lung, and colon tissues.

Post-translational modifications. ATM/ATR-mediated phosphorylation at Thr-454 upon DNA damage promotes binding to SIRT1. Phosphorylation at Thr-454 promotes its sumoylation by switching the binding partner of CCAR2 from SENP1 to PIAS3. Acetylation at Lys-112 and Lys-215 by KAT8 prevents inhibitory binding to SIRT1 and increases its deacetylase activity. Genotoxic stress induces its sumoylation and sumoylation promotes the SIRT1-CCAR2 interaction which in turn inhibits SIRT1-mediated deacetylation of p53/TP53. Sumoylation leads to transcriptional activation of p53/TP53 by sequestering SIRT1 from p53/TP53. Desumoylated by SENP1.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8N163-1	1	yes
Q8N163-2	2

RefSeq proteins (4): NP_001349997, NP_001349998, NP_001380926, NP_066997 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR025223	S1-like_RNA-bd_dom	Domain
IPR025224	CCAR1/CCAR2	Family
IPR025954	DBC1/CARP1_inactive_NUDIX	Domain
IPR045353	LAIKA	Domain

Pfam: PF14443, PF14444, PF19256

UniProt features (47 total): modified residue 16, region of interest 6, mutagenesis site 6, strand 6, compositionally biased region 3, sequence conflict 3, cross-link 2, chain 1, splice variant 1, turn 1, helix 1, coiled-coil region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8EZ6	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N163-F1	69.61	0.37

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 (18): 35, 112, 123, 124, 180, 215, 454, 484, 569, 627, 675, 678, 681, 687, 808, 897, 591, 591

Mutagenesis-validated functional residues (6):

Position	Phenotype
243–264	abolishes binding to sirt1.
454	significantly reduces association with sirt1. decreases sumoylation and the interaction of the sumoylated form with sirt
454	significantly increases association with sirt1 and induces p53 acetylation and apoptosis. increases sumoylation and the
591	loss of sumoylation.
667	no effect on sumoylation.
839	no effect on sumoylation.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-3371453	Regulation of HSF1-mediated heat shock response
R-HSA-2262752	Cellular responses to stress
R-HSA-3371556	Cellular response to heat stress
R-HSA-8953897	Cellular responses to stimuli

MSigDB gene sets: 253 (showing top): GOBP_CIRCADIAN_RHYTHM, GOBP_REGULATION_OF_CELL_CYCLE_CHECKPOINT, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, MODULE_255, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, GOBP_REGULATION_OF_PROTEIN_DEACETYLATION, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_MACROMOLECULE_DEACYLATION, GOBP_GROWTH, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MODULE_317, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_IN_RESPONSE_TO_DNA_DAMAGE

GO Biological Process (21): mRNA processing (GO:0006397), DNA damage response (GO:0006974), RNA splicing (GO:0008380), response to UV (GO:0009411), Wnt signaling pathway (GO:0016055), negative regulation of cell growth (GO:0030308), regulation of protein stability (GO:0031647), negative regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032435), regulation of DNA-templated transcription elongation (GO:0032784), regulation of circadian rhythm (GO:0042752), positive regulation of apoptotic process (GO:0043065), negative regulation of catalytic activity (GO:0043086), mitochondrial fragmentation involved in apoptotic process (GO:0043653), negative regulation of DNA-templated transcription (GO:0045892), rhythmic process (GO:0048511), positive regulation of canonical Wnt signaling pathway (GO:0090263), regulation of protein deacetylation (GO:0090311), negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage (GO:1902230), positive regulation of DNA damage checkpoint (GO:2000003), regulation of DNA-templated transcription (GO:0006355), apoptotic process (GO:0006915)

GO Molecular Function (7): adenyl-nucleotide exchange factor activity (GO:0000774), RNA polymerase II complex binding (GO:0000993), RNA binding (GO:0003723), enzyme inhibitor activity (GO:0004857), enzyme binding (GO:0019899), obsolete unfolded protein binding (GO:0051082), protein binding (GO:0005515)

GO Cellular Component (8): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrial matrix (GO:0005759), spindle (GO:0005819), DBIRD complex (GO:0044609), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Cellular response to heat stress	1
Cellular responses to stimuli	1
Cellular responses to stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
RNA processing	2
regulation of DNA-templated transcription	2
catalytic activity	2
DNA-templated transcription	2
intracellular membraneless organelle	2
mRNA metabolic process	1
cellular response to stress	1
response to light stimulus	1
cell surface receptor signaling pathway	1
regulation of cell growth	1
cell growth	1
negative regulation of growth	1
negative regulation of cellular process	1
regulation of biological quality	1
regulation of proteasomal ubiquitin-dependent protein catabolic process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
negative regulation of proteasomal protein catabolic process	1
negative regulation of ubiquitin-dependent protein catabolic process	1
DNA-templated transcription elongation	1
circadian rhythm	1
regulation of biological process	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
negative regulation of molecular function	1
regulation of catalytic activity	1
apoptotic mitochondrial changes	1
negative regulation of RNA biosynthetic process	1
biological_process	1
positive regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
protein deacetylation	1
regulation of protein modification process	1
intrinsic apoptotic signaling pathway in response to DNA damage	1
regulation of intrinsic apoptotic signaling pathway in response to DNA damage	1
negative regulation of intrinsic apoptotic signaling pathway	1
DNA damage checkpoint signaling	1
positive regulation of cell cycle checkpoint	1

Protein interactions and networks

STRING

2216 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CCAR2	SIRT1	Q96EB6	977
CCAR2	ZNF326	Q5BKZ1	808
CCAR2	RPS19BP1	Q86WX3	771
CCAR2	TP53	P04637	624
CCAR2	SUV39H1	O43463	609
CCAR2	HNRNPA1	P09651	487
CCAR2	ZNF385A	Q96PM9	478
CCAR2	ZNF236	Q9UL36	477
CCAR2	BRD2	P25440	475
CCAR2	SNW1	Q13573	463
CCAR2	E4F1	Q66K89	455
CCAR2	SIRT7	Q9NRC8	454
CCAR2	SIRT6	Q8N6T7	452
CCAR2	USP7	Q93009	450
CCAR2	PRMT1	Q99873	446

IntAct

259 interactions, top by confidence:

A	B	Type	Score
ASH2L	RBBP5	psi-mi:“MI:0914”(association)	0.980
PPP2R2A	PPP2R1A	psi-mi:“MI:2364”(proximity)	0.970
SIRT1	CCAR2	psi-mi:“MI:0915”(physical association)	0.770
SIRT1	CCAR2	psi-mi:“MI:0407”(direct interaction)	0.770
MYC	CCAR2	psi-mi:“MI:0915”(physical association)	0.750
CCAR2	MYC	psi-mi:“MI:0915”(physical association)	0.750
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CEP170P1	SNAPIN	psi-mi:“MI:0915”(physical association)	0.670
RAF1	CALU	psi-mi:“MI:0914”(association)	0.640
CCAR2	ZNF335	psi-mi:“MI:0915”(physical association)	0.620
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610

BioGRID (486): CEP170P1 (Two-hybrid), CCAR2 (Affinity Capture-MS), CCAR2 (Affinity Capture-MS), CCAR2 (Affinity Capture-MS), HSPA8 (Affinity Capture-MS), HSPA1L (Affinity Capture-MS), KCNAB2 (Affinity Capture-MS), HAO1 (Affinity Capture-MS), CEP170 (Affinity Capture-MS), TUBA1A (Affinity Capture-MS), TUBB3 (Affinity Capture-MS), TUBB8 (Affinity Capture-MS), MCC (Affinity Capture-MS), CCAR2 (Affinity Capture-MS), SIRT1 (Affinity Capture-Western)

ESM2 similar proteins: A0JN53, A1L3T7, C9JE40, D2I4M3, G3HQ82, O43299, O75800, O94812, P58660, Q0P5G1, Q15572, Q1RMI8, Q1W1Y5, Q3T1I9, Q3U829, Q56B11, Q571B6, Q58CQ5, Q5ND34, Q5R8S0, Q66H85, Q6NZL6, Q6ZNJ1, Q6ZQA0, Q76MJ5, Q80TE0, Q80UU1, Q80UW5, Q8BGI5, Q8BMG1, Q8C3R1, Q8C3S2, Q8C7B8, Q8CE13, Q8IZL8, Q8N163, Q8VDP4, Q8WXE1, Q96HA7, Q9BQG0

Diamond homologs: Q5R8S0, Q641G3, Q8CH18, Q8IX12, Q8N163, Q8VDP4, F4IS91

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
ATM	“up-regulates activity”	CCAR2	phosphorylation
ATR	“up-regulates activity”	CCAR2	phosphorylation
CCAR2	“down-regulates activity”	SIRT1	binding
CSNK2A1	“up-regulates activity”	CCAR2	phosphorylation
CSNK2A2	“up-regulates activity”	CCAR2	phosphorylation
CCAR2	“down-regulates activity”	SUV39H1	binding
CCAR2	“down-regulates activity”	HDAC3	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 199 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
RIP-mediated NFkB activation via ZBP1	5	23.8×	5e-04
Mitotic Prophase	5	13.1×	2e-03
TAK1-dependent IKK and NF-kappa-B activation	6	12.8×	6e-04
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	5	12.7×	2e-03
TNFR1-induced NF-kappa-B signaling pathway	5	11.9×	2e-03
Activation of NF-kappaB in B cells	8	11.2×	5e-04
Dectin-1 mediated noncanonical NF-kB signaling	7	10.7×	6e-04
AUF1 (hnRNP D0) binds and destabilizes mRNA	6	10.6×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
animal organ development	5	20.5×	7e-04
intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	5	13.8×	3e-03
canonical NF-kappaB signal transduction	6	12.3×	1e-03
tumor necrosis factor-mediated signaling pathway	6	11.1×	2e-03
translational initiation	5	10.0×	9e-03
negative regulation of translation	8	8.8×	7e-04
cellular response to hydrogen peroxide	6	7.8×	8e-03
positive regulation of translation	6	7.6×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	137
Likely benign	26
Benign	14

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2499083	GRCh37/hg19 8p21.3-21.2(chr8:21925038-26372195)x1	Likely pathogenic

SpliceAI

3470 predictions. Top by Δscore:

Variant	Effect	Δscore
8:22605726:T:A	acceptor_gain	1.0000
8:22606454:G:GT	donor_gain	1.0000
8:22606694:C:G	donor_gain	1.0000
8:22606908:A:AG	acceptor_gain	1.0000
8:22606909:G:GG	acceptor_gain	1.0000
8:22606909:GT:G	acceptor_gain	1.0000
8:22607324:GC:G	donor_gain	1.0000
8:22612993:T:A	acceptor_gain	1.0000
8:22612999:T:TA	acceptor_gain	1.0000
8:22614090:A:AG	acceptor_gain	1.0000
8:22614091:G:GA	acceptor_gain	1.0000
8:22614091:GCCCC:G	acceptor_gain	1.0000
8:22614310:CGAAG:C	donor_loss	1.0000
8:22614311:GAAGG:G	donor_loss	1.0000
8:22614312:AAGG:A	donor_loss	1.0000
8:22614313:AGGTA:A	donor_loss	1.0000
8:22614314:GGTA:G	donor_loss	1.0000
8:22614315:GT:G	donor_loss	1.0000
8:22614836:A:AG	acceptor_gain	1.0000
8:22614837:G:GA	acceptor_gain	1.0000
8:22614837:GTTTT:G	acceptor_gain	1.0000
8:22614999:GTG:G	donor_gain	1.0000
8:22615421:GCA:G	acceptor_loss	1.0000
8:22615422:CAGGT:C	acceptor_loss	1.0000
8:22615423:A:T	acceptor_loss	1.0000
8:22615423:AGGT:A	acceptor_gain	1.0000
8:22615424:G:GT	acceptor_loss	1.0000
8:22615424:GGTG:G	acceptor_gain	1.0000
8:22615585:G:GT	donor_gain	1.0000
8:22615593:AGGGG:A	donor_loss	1.0000

AlphaMissense

5961 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:22606628:T:C	F58L	1.000
8:22606629:T:C	F58S	1.000
8:22606629:T:G	F58C	1.000
8:22606630:C:A	F58L	1.000
8:22606630:C:G	F58L	1.000
8:22606634:G:C	G60R	1.000
8:22606634:G:T	G60C	1.000
8:22606635:G:A	G60D	1.000
8:22606635:G:T	G60V	1.000
8:22606641:T:A	V62D	1.000
8:22606661:T:C	F69L	1.000
8:22606663:T:A	F69L	1.000
8:22606663:T:G	F69L	1.000
8:22606664:G:A	G70R	1.000
8:22606664:G:C	G70R	1.000
8:22606664:G:T	G70W	1.000
8:22606665:G:A	G70E	1.000
8:22606671:T:A	V72E	1.000
8:22606673:G:C	D73H	1.000
8:22606674:A:T	D73V	1.000
8:22606683:T:A	V76D	1.000
8:22606688:T:C	F78L	1.000
8:22606689:T:C	F78S	1.000
8:22606690:T:A	F78L	1.000
8:22606690:T:G	F78L	1.000
8:22606920:G:C	G85R	1.000
8:22606929:C:T	P88S	1.000
8:22606930:C:A	P88H	1.000
8:22606930:C:G	P88R	1.000
8:22606948:T:A	V94E	1.000

dbSNP variants (sampled 300 via entrez): RS1000022196 (8:22620118 C>T), RS1000042341 (8:22608942 T>C), RS1000053184 (8:22619963 C>T), RS1000178075 (8:22605994 G>A), RS1000503478 (8:22616378 C>A,T), RS1000656101 (8:22611432 A>G), RS1000854562 (8:22614691 G>T), RS1001203301 (8:22620403 T>C), RS1001415554 (8:22609711 T>C), RS1001437558 (8:22618256 C>A), RS1001446961 (8:22621041 G>A), RS1001909228 (8:22607587 C>A,T), RS1002018861 (8:22619698 C>A,G,T), RS1002282920 (8:22611923 T>C), RS1002359999 (8:22616774 C>G,T)

Disease associations

OMIM: gene MIM:607359 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST000062_3	Multiple sclerosis	8.000000e-06
GCST000567_3	Parkinson’s disease	1.000000e-06
GCST002540_1	Osteoarthritis biomarkers	1.000000e-06
GCST002573_3	Height	8.000000e-07
GCST003064_9	Exploratory eye movement dysfunction in schizophrenia (cognitive search score)	4.000000e-06
GCST003065_7	Exploratory eye movement dysfunction in schizophrenia (responsive search score)	8.000000e-06
GCST003075_137	Cognitive decline rate in late mild cognitive impairment	8.000000e-07
GCST003075_138	Cognitive decline rate in late mild cognitive impairment	3.000000e-07
GCST003075_139	Cognitive decline rate in late mild cognitive impairment	8.000000e-07
GCST003075_16	Cognitive decline rate in late mild cognitive impairment	1.000000e-06
GCST003075_35	Cognitive decline rate in late mild cognitive impairment	6.000000e-07
GCST003075_36	Cognitive decline rate in late mild cognitive impairment	2.000000e-07
GCST003264_32	Post bronchodilator FEV1/FVC ratio	4.000000e-06
GCST003992_32	Photic sneeze reflex	8.000000e-34
GCST008103_124	Bipolar disorder	5.000000e-06
GCST90014033_86	Haemorrhoidal disease	3.000000e-10

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0005890	osteoarthritis biomarker measurement
EFO:0007700	exploratory eye movement measurement
EFO:0007710	cognitive decline measurement
EFO:0004713	FEV/FVC ratio
EFO:0007887	autosomal dominant compelling helio-ophthalmic outburst syndrome

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5483141 (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: 5,325 (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
CHEMBL1232461	MOLIBRESIB	2	1,538
CHEMBL14762	SELICICLIB	2	3,787

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.85	Kd	14.26	nM	CHEMBL5653589
7.85	ED50	14.26	nM	CHEMBL5653589
6.42	IC50	380	nM	MOLIBRESIB
5.49	Kd	3261	nM	SELICICLIB

PubChem BioAssay actives

2 with measured affinity, of 8 total; 2 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148006: Binding affinity to human CCAR2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0143	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178960: Inhibition of KIAA1967 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.3800	uM

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression	4
sodium arsenite	decreases expression, increases abundance, increases expression	2
Doxorubicin	decreases expression, decreases phosphorylation	2
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
beauvericin	decreases expression	1
methylmercuric chloride	decreases expression	1
beta-lapachone	increases expression	1
perfluorooctanoic acid	decreases expression	1
aflatoxin B2	increases methylation	1
mercuric bromide	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
perfluorohexanesulfonic acid	decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	decreases expression	1
bisphenol AF	increases expression	1
Arsenic	increases abundance, decreases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	increases phosphorylation	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ivermectin	decreases expression	1
Mustard Gas	increases phosphorylation	1
Ribonucleotides	affects binding	1
Cadmium Chloride	decreases expression	1
Vitamin K 3	affects expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5472096	Binding	Selectivity interaction (Competition-binding assay (Kinases and other enzymes) ) EUB0000650a CCAR2	Selectivity Literature for EUbOPEN Chemogenomic Library

Clinical trials (associated diseases)

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