CCAR2_PONAB
ID CCAR2_PONAB Reviewed; 918 AA.
AC Q5R8S0; Q5RE39;
DT 24-JAN-2006, integrated into UniProtKB/Swiss-Prot.
DT 21-DEC-2004, sequence version 1.
DT 25-MAY-2022, entry version 81.
DE RecName: Full=Cell cycle and apoptosis regulator protein 2;
DE AltName: Full=Cell division cycle and apoptosis regulator protein 2;
GN Name=CCAR2;
OS Pongo abelii (Sumatran orangutan) (Pongo pygmaeus abelii).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Pongo.
OX NCBI_TaxID=9601;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney;
RG The German cDNA consortium;
RL Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Core component of the DBIRD complex, a multiprotein complex
CC that acts at the interface between core mRNP particles and RNA
CC polymerase II (RNAPII) and integrates transcript elongation with the
CC regulation of alternative splicing: the DBIRD complex affects local
CC transcript elongation rates and alternative splicing of a large set of
CC exons embedded in (A + T)-rich DNA regions (By similarity). Inhibits
CC SIRT1 deacetylase activity leading to increasing levels of p53/TP53
CC acetylation and p53-mediated apoptosis (By similarity). Inhibits
CC SUV39H1 methyltransferase activity (By similarity). Mediates ligand-
CC dependent transcriptional activation by nuclear hormone receptors (By
CC similarity). Plays a critical role in maintaining genomic stability and
CC cellular integrity following UV-induced genotoxic stress (By
CC similarity). Regulates the circadian expression of the core clock
CC components NR1D1 and ARNTL/BMAL1 (By similarity). Enhances the
CC transcriptional repressor activity of NR1D1 through stabilization of
CC NR1D1 protein levels by preventing its ubiquitination and subsequent
CC degradation (By similarity). Represses the ligand-dependent
CC transcriptional activation function of ESR2 (By similarity). Acts as a
CC regulator of PCK1 expression and gluconeogenesis by a mechanism that
CC involves, at least in part, both NR1D1 and SIRT1 (By similarity).
CC Negatively regulates the deacetylase activity of HDAC3 and can alter
CC its subcellular localization (By similarity). Positively regulates the
CC beta-catenin pathway (canonical Wnt signaling pathway) and is required
CC for MCC-mediated repression of the beta-catenin pathway (By
CC similarity). Represses ligand-dependent transcriptional activation
CC function of NR1H2 and NR1H3 and inhibits the interaction of SIRT1 with
CC NR1H3 (By similarity). Plays an important role in tumor suppression
CC through p53/TP53 regulation; stabilizes p53/TP53 by affecting its
CC interaction with ubiquitin ligase MDM2 (By similarity). Represses the
CC transcriptional activator activity of BRCA1 (By similarity). Inhibits
CC SIRT1 in a CHEK2 and PSEM3-dependent manner and inhibits the activity
CC of CHEK2 in vitro (By similarity). {ECO:0000250|UniProtKB:Q8N163}.
CC -!- SUBUNIT: Component of the DBIRD complex (By similarity). Interacts with
CC ZNF326/ZIRD; the interaction is direct (By similarity). Interacts (via
CC N-terminus) with SIRT1, which inhibits the deacetylation of substrates
CC (By similarity). Interacts (via N-terminus) with SUV39H1; this
CC interaction abolishes the interaction with SIRT1 (By similarity).
CC Component of a nuclear receptor-mediated transcription complex composed
CC of at least ZNF335, CCAR2 and EMSY; the complex stimulates the
CC transcription of nuclear receptor target genes such as SOX9 and HOXA1
CC (By similarity). Within the complex interacts with EMSY and interacts
CC with ZNF335 (via C-terminus) (By similarity). Components of this
CC complex may associate with components of a histone methylation complex
CC to form a complex at least composed of ZNF335, HCFC1, CCAR2, EMSY,
CC MKI67, RBBP5, ASH2L and WDR5 (By similarity). Within this complex,
CC interacts with ASH2L (By similarity). Interacts with NR1D1 (By
CC similarity). Interacts (via N-terminus) with ESR1 and ESR2 (By
CC similarity). Interacts (via N-terminus) with HDAC3 (via C-terminus) (By
CC similarity). Interacts with HDAC1 and MED2F (By similarity). Interacts
CC with MCC (By similarity). Interacts (via N-terminus) with NR1H2 and
CC NR1H3 in a ligand-independent manner (By similarity). Interacts with
CC CSNK2A1 (By similarity). Interacts (via N-terminus) with p53/TP53 (By
CC similarity). Interacts (via N-terminus) with BRCA1 (via the BRCT
CC domains) (By similarity). Interacts (via N-terminus) with CHEK2 (via
CC protein kinase domain) (By similarity). Interacts with PSEM3 (By
CC similarity). Interacts (via N-terminus) with PSIA3 and SENP1 (By
CC similarity). The sumoylated form shows a preferential interaction with
CC SIRT1 as compared to its unmodified form (By similarity).
CC {ECO:0000250|UniProtKB:Q8N163}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q8N163}. Cytoplasm
CC {ECO:0000250|UniProtKB:Q8N163}. Cytoplasm, cytoskeleton, spindle
CC {ECO:0000250|UniProtKB:Q8N163}. Note=Recruited to chromatin, post-UV
CC irradiation. Sequestered to the cytoplasm in the presence of MCC.
CC Translocated to the cytoplasm during UV-induced apoptosis.
CC {ECO:0000250|UniProtKB:Q8N163}.
CC -!- PTM: ATM/ATR-mediated phosphorylation at Thr-454 upon DNA damage
CC promotes binding to SIRT1. Phosphorylation at Thr-454 promotes its
CC sumoylation by switching the binding partner of CCAR2 from SENP1 to
CC PIAS3. {ECO:0000250|UniProtKB:Q8N163}.
CC -!- PTM: Acetylation at Lys-112 and Lys-215 by KAT8 prevents inhibitory
CC binding to SIRT1 and increases its deacetylase activity.
CC {ECO:0000250|UniProtKB:Q8N163}.
CC -!- PTM: Genotoxic stress induces its sumoylation and sumoylation promotes
CC the SIRT1-CCAR2 interaction which in turn inhibits SIRT1-mediated
CC deacetylation of p53/TP53. Sumoylation leads to transcriptional
CC activation of p53/TP53 by sequestering SIRT1 from p53/TP53.
CC Desumoylated by SENP1. {ECO:0000250|UniProtKB:Q8N163}.
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DR EMBL; CR859680; CAH91840.1; -; mRNA.
DR EMBL; CR857699; CAH89968.1; -; mRNA.
DR AlphaFoldDB; Q5R8S0; -.
DR SMR; Q5R8S0; -.
DR STRING; 9601.ENSPPYP00000020648; -.
DR PRIDE; Q5R8S0; -.
DR eggNOG; KOG4246; Eukaryota.
DR Proteomes; UP000001595; Unplaced.
DR GO; GO:0000785; C:chromatin; ISS:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0044609; C:DBIRD complex; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0005819; C:spindle; ISS:UniProtKB.
DR GO; GO:0004857; F:enzyme inhibitor activity; ISS:UniProtKB.
DR GO; GO:0000993; F:RNA polymerase II complex binding; ISS:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IEA:UniProtKB-KW.
DR GO; GO:0006397; P:mRNA processing; IEA:UniProtKB-KW.
DR GO; GO:0030308; P:negative regulation of cell growth; ISS:UniProtKB.
DR GO; GO:1902230; P:negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage; ISS:UniProtKB.
DR GO; GO:0032435; P:negative regulation of proteasomal ubiquitin-dependent protein catabolic process; ISS:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:0090263; P:positive regulation of canonical Wnt signaling pathway; ISS:UniProtKB.
DR GO; GO:2000003; P:positive regulation of DNA damage checkpoint; ISS:UniProtKB.
DR GO; GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB.
DR GO; GO:0032784; P:regulation of DNA-templated transcription, elongation; ISS:UniProtKB.
DR GO; GO:0031647; P:regulation of protein stability; ISS:UniProtKB.
DR GO; GO:0009411; P:response to UV; ISS:UniProtKB.
DR GO; GO:0048511; P:rhythmic process; IEA:UniProtKB-KW.
DR GO; GO:0008380; P:RNA splicing; ISS:UniProtKB.
DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW.
DR InterPro; IPR045354; BURAN.
DR InterPro; IPR025224; CCAR1/CCAR2.
DR InterPro; IPR028811; CCAR2.
DR InterPro; IPR025954; DBC1/CARP1_inactive_NUDIX_dom.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR045353; LAIKA.
DR InterPro; IPR025223; S1-like_RNA-bd_dom.
DR PANTHER; PTHR14304; PTHR14304; 1.
DR PANTHER; PTHR14304:SF12; PTHR14304:SF12; 1.
DR Pfam; PF19257; BURAN; 1.
DR Pfam; PF14443; DBC1; 1.
DR Pfam; PF19256; LAIKA; 1.
DR Pfam; PF14444; S1-like; 1.
DR SMART; SM01122; DBC1; 1.
DR SUPFAM; SSF47473; SSF47473; 1.
PE 2: Evidence at transcript level;
KW Acetylation; Activator; Apoptosis; Biological rhythms; Cell cycle;
KW Coiled coil; Cytoplasm; Cytoskeleton; DNA damage; Isopeptide bond;
KW Metalloenzyme inhibitor; Methylation; mRNA processing; mRNA splicing;
KW Nucleus; Phosphoprotein; Reference proteome; Repressor; Transcription;
KW Transcription regulation; Tumor suppressor; Ubl conjugation;
KW Wnt signaling pathway.
FT CHAIN 1..918
FT /note="Cell cycle and apoptosis regulator protein 2"
FT /id="PRO_0000050815"
FT REGION 1..35
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 179..219
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 446..510
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 568..637
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 605..665
FT /note="Interaction with MCC"
FT /evidence="ECO:0000250|UniProtKB:Q8N163"
FT REGION 699..918
FT /note="Interaction with NR1D1"
FT /evidence="ECO:0000250|UniProtKB:Q8N163"
FT COILED 824..904
FT /evidence="ECO:0000255"
FT COMPBIAS 14..28
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 190..219
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 471..496
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 569..601
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 622..637
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 35
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q8N163"
FT MOD_RES 112
FT /note="N6-acetyllysine; by KAT8"
FT /evidence="ECO:0000250|UniProtKB:Q8N163"
FT MOD_RES 123
FT /note="N6-methyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q8N163"
FT MOD_RES 124
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8N163"
FT MOD_RES 180
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0000250|UniProtKB:Q8N163"
FT MOD_RES 215
FT /note="N6-acetyllysine; by KAT8"
FT /evidence="ECO:0000250|UniProtKB:Q8N163"
FT MOD_RES 454
FT /note="Phosphothreonine; by ATM, ATR and CK2"
FT /evidence="ECO:0000250|UniProtKB:Q8N163"
FT MOD_RES 484
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q8N163"
FT MOD_RES 569
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8N163"
FT MOD_RES 622
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8N163"
FT MOD_RES 670
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8N163"
FT MOD_RES 673
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8N163"
FT MOD_RES 676
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8N163"
FT MOD_RES 682
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8N163"
FT MOD_RES 803
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8N163"
FT MOD_RES 892
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q8N163"
FT CROSSLNK 586
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2 and SUMO3); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q8N163"
FT CROSSLNK 586
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q8N163"
FT CONFLICT 68
FT /note="Y -> C (in Ref. 1; CAH89968)"
FT /evidence="ECO:0000305"
FT CONFLICT 151
FT /note="Q -> R (in Ref. 1; CAH89968)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 918 AA; 102226 MW; FB5B0FF54AD60B6D CRC64;
MSQFKRQRIN PLPGGRNFSG TASTSLLGPP PGLLTPPVAT ELSQNARHLQ GGEKQRVFTG
IVTSLHDYFG VVDEEVFFQL SVVKGRLPQL GEKVLVKAAY NPGQAVPWNA VKVQTLSNQP
LLKSPAPPLL HVAALGQKQG ILGAQPQLIF QPHRIPPLFP QKPLSLFQTS HTLHLSHLNR
FPARGPHGRL DQGQSDDYDS KKRKQRAGGE PWGAKKPRHD LPPYRVHLTP YTVDSPICDF
LELQRRYRSL LVPSDFLSVH LSWLSAFPLS QPFSLHHPSR IQVSSEKEAA PDAGAEPIPA
DSDPAYSSKV LLLSSPGLEE LYRCCMLFVD DMAEPRETPE HPLKQIKFLL GRKEEEAVLV
GGEWSPSLDG LDPQADPQVL VRTAIRCAQA QTGIDLSGCT KWWRFAEFQY LQPGPPRRLQ
TVVVYLPDVW TIMPTLEEWE ALCQQKAAEA APPTQEAPGE TEPTEQAPDA LEQAADTSRQ
NAETPEATTQ QETDTDLPEA PPPPLEPAVI ARPGCVNLSL HGIVEDRRPK ERISFEVMVL
AELFLEMLQR DFGYRVYKML LSLPEKVVSP PEPEKEEAAK EEEAIKEEVV KEPKDEAQNE
GPATESEAPL KEDGLLPKPP SSGGEEEEKP RGEASEDLCE MALDPELLLL RDDGEEEFAG
AKLEDSEVRS VASNQSEMEF SSLQDMPKEL DPSAVLPLDC LLAFVFFDAN WCGYLHRRDL
ERILLTLGIR LSAEQAKQLV SRVVTQNICQ YRSLQYSRQE GLDGGLPEEV LFGNLDLLPP
SGKSTKPGAA PTEHKALVSH NGSLINVGSL LQRAEQQDSG RLYLENRIHT LELKLEESHN
RFSATEVTNK TLAAEMQELR ARLAEAEETA RTAERQKSQL QRLLQELRRR LTPLQLEIQR
VVEKADSWVE KEEPAPSN
