MDC1_RAT
ID MDC1_RAT Reviewed; 1279 AA.
AC Q5U2M8; Q6MG15;
DT 05-JUL-2005, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2005, sequence version 2.
DT 03-AUG-2022, entry version 133.
DE RecName: Full=Mediator of DNA damage checkpoint protein 1;
GN Name=Mdc1;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Brown Norway;
RX PubMed=15060004; DOI=10.1101/gr.1987704;
RA Hurt P., Walter L., Sudbrak R., Klages S., Mueller I., Shiina T., Inoko H.,
RA Lehrach H., Guenther E., Reinhardt R., Himmelbauer H.;
RT "The genomic sequence and comparative analysis of the rat major
RT histocompatibility complex.";
RL Genome Res. 14:631-639(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Brown Norway; TISSUE=Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-168; SER-176; SER-298;
RP SER-350; SER-354; THR-356; SER-380; THR-382; SER-411; SER-421; SER-438;
RP THR-440; SER-550; SER-587; SER-589; SER-793 AND SER-801, AND IDENTIFICATION
RP BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
CC -!- FUNCTION: Required for checkpoint mediated cell cycle arrest in
CC response to DNA damage within both the S phase and G2/M phases of the
CC cell cycle. May serve as a scaffold for the recruitment of DNA repair
CC and signal transduction proteins to discrete foci of DNA damage marked
CC by 'Ser-139' phosphorylation of histone H2AX. Also required for
CC downstream events subsequent to the recruitment of these proteins.
CC These include phosphorylation and activation of the ATM, CHEK1 and
CC CHEK2 kinases, and stabilization of TP53 and apoptosis. ATM and CHEK2
CC may also be activated independently by a parallel pathway mediated by
CC TP53BP1 (By similarity). {ECO:0000250}.
CC -!- SUBUNIT: Homodimer. Interacts with several proteins involved in the DNA
CC damage response, although not all these interactions may be direct.
CC Interacts with H2AX, which requires phosphorylation of H2AX. Interacts
CC with the MRN complex, composed of MRE11, RAD50, and NBN. This
CC interaction is independent of DNA and does not appear to be regulated
CC by phosphorylation of MDC1. Interacts with CHEK2, which is also
CC independent of DNA and requires ATM-mediated phosphorylation within the
CC FHA domain of CHEK2. Interacts constitutively with the BRCA1-BARD1
CC complex, SMC1A and TP53BP1. Interacts with ATM and FANCD2, and these
CC interactions are reduced upon DNA damage. Also interacts with the PRKDC
CC complex, composed of XRCC6/KU70, XRCC5/KU80 and PRKDC/XRCC7. This
CC interaction may be required for PRKDC autophosphorylation, which is
CC essential for DNA double strand break (DSB) repair. When phosphorylated
CC by ATM, interacts with RNF8 (via FHA domain). Interacts with CEP164.
CC When phosphorylated, interacts with APTX (via FHA-like domain) (By
CC similarity). {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250}. Chromosome {ECO:0000250}.
CC Note=Associated with chromatin. Relocalizes to discrete nuclear foci
CC following DNA damage, this requires phosphorylation of H2AX.
CC Colocalizes with APTX at sites of DNA double-strand breaks (By
CC similarity). {ECO:0000250}.
CC -!- DOMAIN: Tandemly repeated BRCT domains are characteristic of proteins
CC involved in DNA damage signaling. In MDC1, these repeats are required
CC for localization to chromatin which flanks sites of DNA damage marked
CC by 'Ser-139' phosphorylation of H2AX (By similarity). {ECO:0000250}.
CC -!- PTM: Phosphorylated upon exposure to ionizing radiation (IR),
CC ultraviolet radiation (UV), and hydroxyurea (HU). Phosphorylation in
CC response to IR requires ATM, NBN, and possibly CHEK2. Also
CC phosphorylated during the G2/M phase of the cell cycle and during
CC activation of the mitotic spindle checkpoint. Phosphorylation at Thr-4
CC by ATM stabilizes and enhances homodimerization via the FHA domain (By
CC similarity). {ECO:0000250}.
CC -!- PTM: Sumoylation at Lys-1034 by PIAS4 following DNA damage promotes
CC ubiquitin-mediated degradation. {ECO:0000250}.
CC -!- PTM: Ubiquitinated by RNF4, leading to proteasomal degradation;
CC undergoes 'Lys-48'-linked polyubiquitination. {ECO:0000250}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH85955.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=CAE84032.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; BX883048; CAE84032.1; ALT_SEQ; Genomic_DNA.
DR EMBL; BC085955; AAH85955.1; ALT_INIT; mRNA.
DR RefSeq; NP_001159747.1; NM_001166275.1.
DR AlphaFoldDB; Q5U2M8; -.
DR SMR; Q5U2M8; -.
DR STRING; 10116.ENSRNOP00000049009; -.
DR iPTMnet; Q5U2M8; -.
DR PhosphoSitePlus; Q5U2M8; -.
DR PaxDb; Q5U2M8; -.
DR PRIDE; Q5U2M8; -.
DR Ensembl; ENSRNOT00000046798; ENSRNOP00000049009; ENSRNOG00000032813.
DR GeneID; 309595; -.
DR KEGG; rno:309595; -.
DR UCSC; RGD:1559468; rat.
DR CTD; 9656; -.
DR RGD; 1559468; Mdc1.
DR eggNOG; KOG2043; Eukaryota.
DR GeneTree; ENSGT00940000161757; -.
DR HOGENOM; CLU_003038_0_0_1; -.
DR InParanoid; Q5U2M8; -.
DR OMA; HGDCETD; -.
DR OrthoDB; 670424at2759; -.
DR PhylomeDB; Q5U2M8; -.
DR PRO; PR:Q5U2M8; -.
DR Proteomes; UP000002494; Chromosome 20.
DR Bgee; ENSRNOG00000032813; Expressed in testis and 18 other tissues.
DR Genevisible; Q5U2M8; RN.
DR GO; GO:0005694; C:chromosome; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISO:RGD.
DR GO; GO:0070975; F:FHA domain binding; ISO:RGD.
DR GO; GO:0008022; F:protein C-terminus binding; ISO:RGD.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0006281; P:DNA repair; IEA:UniProtKB-KW.
DR CDD; cd00060; FHA; 1.
DR Gene3D; 3.40.50.10190; -; 2.
DR InterPro; IPR001357; BRCT_dom.
DR InterPro; IPR036420; BRCT_dom_sf.
DR InterPro; IPR000253; FHA_dom.
DR InterPro; IPR008984; SMAD_FHA_dom_sf.
DR Pfam; PF00498; FHA; 1.
DR Pfam; PF16770; RTT107_BRCT_5; 1.
DR SMART; SM00292; BRCT; 2.
DR SMART; SM00240; FHA; 1.
DR SUPFAM; SSF49879; SSF49879; 1.
DR SUPFAM; SSF52113; SSF52113; 2.
DR PROSITE; PS50172; BRCT; 2.
DR PROSITE; PS50006; FHA_DOMAIN; 1.
PE 1: Evidence at protein level;
KW Acetylation; Cell cycle; Chromosome; DNA damage; DNA repair;
KW Isopeptide bond; Nucleus; Phosphoprotein; Reference proteome; Repeat;
KW Ubl conjugation.
FT CHAIN 1..1279
FT /note="Mediator of DNA damage checkpoint protein 1"
FT /id="PRO_0000096321"
FT DOMAIN 54..105
FT /note="FHA"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00086"
FT DOMAIN 1085..1163
FT /note="BRCT 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00033"
FT DOMAIN 1184..1275
FT /note="BRCT 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00033"
FT REGION 1..150
FT /note="Interaction with CHEK2"
FT /evidence="ECO:0000250"
FT REGION 1..22
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2..222
FT /note="Interaction with the MRN complex"
FT /evidence="ECO:0000250"
FT REGION 156..394
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 409..634
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 714..744
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 772..1086
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1..19
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 179..198
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 218..236
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 304..326
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 353..367
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 434..458
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 477..491
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 601..615
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 617..634
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 797..831
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 842..932
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 941..968
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 985..1015
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1016..1044
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1051..1066
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 4
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q14676"
FT MOD_RES 146
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q14676"
FT MOD_RES 168
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 176
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 298
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 300
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q14676"
FT MOD_RES 314
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q14676"
FT MOD_RES 316
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q14676"
FT MOD_RES 350
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 354
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 356
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 372
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q14676"
FT MOD_RES 380
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 382
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 394
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q14676"
FT MOD_RES 411
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 421
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 434
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q5PSV9"
FT MOD_RES 438
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 440
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 457
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q5PSV9"
FT MOD_RES 466
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q5PSV9"
FT MOD_RES 488
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q5PSV9"
FT MOD_RES 489
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q5PSV9"
FT MOD_RES 550
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 587
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 589
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 730
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q14676"
FT MOD_RES 745
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q14676"
FT MOD_RES 764
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q14676"
FT MOD_RES 793
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 801
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 824
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q14676"
FT MOD_RES 889
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q14676"
FT MOD_RES 951
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q14676"
FT MOD_RES 1008
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q5PSV9"
FT MOD_RES 1009
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q5PSV9"
FT MOD_RES 1012
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q5PSV9"
FT MOD_RES 1016
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q5PSV9"
FT MOD_RES 1054
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q5PSV9"
FT CROSSLNK 991
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q14676"
FT CROSSLNK 1034
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO1); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q14676"
FT CROSSLNK 1034
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q14676"
SQ SEQUENCE 1279 AA; 136948 MW; C89F981C5B08DCAA CRC64;
MENTQVIDWD AEEEEETEIS SGSLGYSVEP IGRLRFFSGT HGPERDFPLY LGKNVVGRSP
DCSVALPFPS ISKQHAVIEI SAWNKAPILQ DCGSLNGTQI VKPPRVLAPG VSHRLRDQEL
ILFADFPCQY HRLNVPPPLV PRSLLTIEKT PRIRGRSQNS RVLLAEDSEE EGDFPSGRSV
ANGSRNTASP SATVVPESDE EGSSPGPSVP GPSSPFGLGS DTDESQGQQP GVEESSLADN
SGAAGEPEQP EVNGVTTGTL AQPTKDKFKD TKMKEEAGSA GVPVGSVVEG SPTLGEDSDT
EADEERQPSG SGDSDTDVEE ERVPVKKNQV LLGVGIGGPG ARGVAHLQDS PTGSDTDVEE
DKTALAAPPE RSHTAMVINS DTDEEERGEE EEVSAALTLA RLKERGIALW SGEPGTEEVK
SQPQVLVERS QSASGRDSDT DVEEGSSGGK REIVPDSPMD VDETLTVTQP ESQPPCRPND
VDEDVDMSSP GSHLEGKKAS SALVDKNRAQ VEEEVPGPSV TLGEKHQVPL EGAQPPEEAR
ETAVQEGSSS PVADIRMSQQ PVAEDAGTEC AAAVSEQKSA LEVGAQSRSP AAPVEQVVVR
TDTSGDPTLP QREGAQTPTG REREAHVGGT KHAKECCDEP EDLCLSATQC FVEGESQHPG
AVQSLEDEPT QVFPCLPQEP GPSHLSLPTP GADTLDVPWE VLATQPFCLR EQTETSEPID
THEAHGSQPS LPGEPPGHQH PVPTSLDHTE LLRIDDREMQ TVEKAMGHLS CQMMPDGKAS
GDDPEPSDHR LFSPVPEASA SPQSLLTSQS QKQSTPQPMF PTSSSELALP ETLHTKPNVR
PRRSSRMTPS PHSSAALKPY TTCPTNQPAA SRPTSRPTRG RANRSSTRTP ELIVPTGPEL
QPSTSTEQPG IPNLTSQVTE GRAHSTSVNM PEPVLTGPEA QPLTSAEQSV TSNLNPRAQP
LTLEPVPQTS HQRRRRATGK QGSRTAPVGP KSYSTPAEPE PQSSASQSSG ASEADSPHQK
RPRRQVTQKT VVVKEEDPGE IQVKEEPQET AIPTPGKRKR DPAEGETQGN PTRSRRTKPN
QEAAAPKVLF TGVVDSRGER AVLALGGSLA SSVNEASHLV TDRIRRTVKF LCAVGKGIPI
LSLNWLYQSR KAGCFLPPDD YLVTDPEQEK NFSFSLRDSL SRARERRLLE DYEIHVTPGV
QPPPPQMGEI ISCCGGTVLP SMPHSYKLHR VVITCTEDLP RCAIASRLGL PLLSPEFLLT
GVLKQEATPE AFVLSNLEM
