CCAR2

CCAR2 (Cell Cycle And Apoptosis Regulator 2) is a Protein Coding gene. Diseases associated with CCAR2 include Estrogen-Receptor Negative Breast Cancer. Among its related pathways are Circadian rythm related genes and Cellular response to heat stress. Gene Ontology (GO) annotations related to this gene include enzyme inhibitor activity. An important paralog of this gene is CCAR1.

cell cycle and apoptosis regulator 2

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 (PubMed:22446626).
Inhibits SIRT1 deacetylase activity leading to increasing levels of p53/TP53 acetylation and p53-mediated apoptosis (PubMed:18235501, PubMed:18235502, PubMed:23352644).
Inhibits SUV39H1 methyltransferase activity (PubMed:19218236).
Mediates ligand-dependent transcriptional activation by nuclear hormone receptors (PubMed:19131338).
Plays a critical role in maintaining genomic stability and cellular integrity following UV-induced genotoxic stress (PubMed:23398316).
Regulates the circadian expression of the core clock components NR1D1 and ARNTL/BMAL1 (PubMed:23398316).
Enhances the transcriptional repressor activity of NR1D1 through stabilization of NR1D1 protein levels by preventing its ubiquitination and subsequent degradation (PubMed:23398316).
Represses the ligand-dependent transcriptional activation function of ESR2 (PubMed:20074560).
Acts as a regulator of PCK1 expression and gluconeogenesis by a mechanism that involves, at least in part, both NR1D1 and SIRT1 (PubMed:24415752).
Negatively regulates the deacetylase activity of HDAC3 and can alter its subcellular localization (PubMed:21030595).
Positively regulates the beta-catenin pathway (canonical Wnt signaling pathway) and is required for MCC-mediated repression of the beta-catenin pathway (PubMed:24824780).
Represses ligand-dependent transcriptional activation function of NR1H2 and NR1H3 and inhibits the interaction of SIRT1 with NR1H3 (PubMed:25661920).
Plays an important role in tumor suppression through p53/TP53 regulation; stabilizes p53/TP53 by affecting its interaction with ubiquitin ligase MDM2 (PubMed:25732823).
Represses the transcriptional activator activity of BRCA1 (PubMed:20160719).
Inhibits SIRT1 in a CHEK2 and PSEM3-dependent manner and inhibits the activity of CHEK2 in vitro (PubMed:25361978).

Cell cycle Source: UniProtKB-KW
Cellular response to DNA damage stimulus Source: UniProtKB-KW
Mitochondrial fragmentation involved in apoptotic process Source: UniProtKB
mRNA processing Source: UniProtKB-KW
Negative regulation of catalytic activity Source: UniProtKB
Negative regulation of cell growth Source: UniProtKB
Negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage Source: UniProtKB
Negative regulation of proteasomal ubiquitin-dependent protein catabolic process Source: UniProtKB
Negative regulation of transcription, DNA-templated Source: UniProtKB
Positive regulation of apoptotic process Source: UniProtKB
Positive regulation of canonical Wnt signaling pathway Source: UniProtKB
Positive regulation of DNA damage checkpoint Source: UniProtKB
Regulation of cellular response to heat Source: Reactome
Regulation of circadian rhythm Source: UniProtKB
Regulation of DNA-templated transcription, elongation Source: UniProtKB
Regulation of protein deacetylation Source: UniProtKB
Regulation of protein stability Source: UniProtKB
Regulation of transcription, DNA-templated Source: GO_Central
Response to UV Source: UniProtKB
Rhythmic process Source: UniProtKB-KW
RNA splicing Source: UniProtKB
Wnt signaling pathway Source: UniProtKB-KW

Spindle; Cytoplasm; Nucleus. Recruited to chromatin, post-UV irradiation. Sequestered to the cytoplasm in the presence of MCC. Translocated to the cytoplasm during UV-induced apoptosis.

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.