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MDC1

Protein FULL name:

mediator of DNA damage checkpoint protein 1 [Homo sapiens].


MDC1 (Homo sapiens) is product of expression of MDC1 gene.


MDC1 is involved in:

DDS in Homo sapiens
     


Keywords:



FUNCTION: Required for checkpoint mediated cell cycle arrest in response to DNA damage within both the S phase and G2/M phases of the cell cycle. May serve as a scaffold for the recruitment of DNA repair and signal transduction proteins to discrete foci of DNA damage marked by 'Ser-139' phosphorylation of histone H2AFX. Also required for downstream events subsequent to the recruitment of these proteins. These include phosphorylation and activation of the ATM, CHEK1/CHK1 and CHEK2/CHK2/CDS1 kinases, and stabilization of TP53 and apoptosis. ATM and CHEK2 may also be activated independently by a parallel pathway mediated by TP53BP1.

SUBUNIT: Interacts with several proteins involved in the DNA damage response, although not all these interactions may be direct. Interacts with H2AFX, which requires phosphorylation of H2AFX on 'Ser-139'. Interacts with the MRN complex, composed of MRE11A/MRE11, RAD50, and NBN. Interacts with CHEK2/CHK2/CDS1, which requires ATM-mediated phosphorylation of 'Thr-68' within the FHA domain of CHEK2. Interacts constitutively with the BRCA1-BARD1 complex, SMC1A and TP53BP1. Interacts with ATM and FANCD2, and these interactions are reduced upon DNA damage. Also interacts with the PRKDC complex, composed of G22P1/KU70, XRCC5/KU80 and PRKDC/XRCC7. This interaction may be required for PRKDC autophosphorylation, which is essential for DNA double strand break (DSB) repair. When phosphorylated by ATM, interacts with RNF8 (via FHA domain). Interacts with CEP164.

INTERACTION: Q13315:ATM; NbExp=1; IntAct=EBI-495644, EBI-495465; P38398:BRCA1; NbExp=1; IntAct=EBI-495644, EBI-349905; P16104:H2AFX; NbExp=3; IntAct=EBI-495644, EBI-494830; O60934:NBN; NbExp=4; IntAct=EBI-495644, EBI-494844; O43070:nbs1 (xeno); NbExp=1; IntAct=EBI-495644, EBI-2125045; O76064:RNF8; NbExp=5; IntAct=EBI-495644, EBI-373337;

SUBCELLULAR LOCATION: Nucleus. Note=Associated with chromatin. Relocalizes to discrete nuclear foci following DNA damage, this requires 'Ser-139' phosphorylation of H2AFX.

TISSUE SPECIFICITY: Highly expressed in testis.

DOMAIN: Tandemly repeated BRCT domains are characteristic of proteins involved in DNA damage signaling. In MDC1, these repeats are required for localization to chromatin which flanks sites of DNA damage marked by 'Ser-139' phosphorylation of H2AFX.

PTM: Phosphorylated upon exposure to ionizing radiation (IR), ultraviolet radiation (UV), and hydroxyurea (HU). Phosphorylation in response to IR requires ATM, NBN, and possibly CHEK2. Also phosphorylated during the G2/M phase of the cell cycle and during activation of the mitotic spindle checkpoint.

SIMILARITY: Contains 2 BRCT domains.

SIMILARITY: Contains 1 FHA domain.

SEQUENCE CAUTION: Sequence=BAA11487.2; Type=Erroneous initiation; Sequence=CAH18685.1; Type=Erroneous termination; Positions=1804; Note=Translated as Gln;


NCBI GenPept GI number(s): 132626688
Species: Homo sapiens

Links to other databases:

Database ID Link
Uniprot Q14676 Q14676
PFAM: - Q14676 (Link - using uniprot id)
InterPro: - Q14676 (Link - using uniprot id)
CATH: None  
SCOP: None  
PDB: - -


Protein sequence:
MEDTQAIDWDVEEEEETEQSSESLRCNVEPVGRLHIFSGAHGPEKDFPLH
LGKNVVGRMPDCSVALPFPSISKQHAEIEILAWDKAPILRDCGSLNGTQI
LRPPKVLSPGVSHRLRDQELILFADLLCQYHRLDVSLPFVSRGPLTVEET
PRVQGETQPQRLLLAEDSEEEVDFLSERRMVKKSRTTSSSVIVPESDEEG
HSPVLGGLGPPFAFNLNSDTDVEEGQQPATEEASSAARRGATVEAKQSEA
EVVTEIQLEKDQPLVKERDNDTKVKRGAGNGVVPAGVILERSQPPGEDSD
TDVDDDSRPPGRPAEVHLERAQPFGFIDSDTDAEEERIPATPVVIPMKKR
KIFHGVGTRGPGAPGLAHLQESQAGSDTDVEEGKAPQAVPLEKSQASMVI
NSDTDDEEEVSAALTLAHLKESQPAIWNRDAEEDMPQRVVLLQRSQTTTE
RDSDTDVEEEELPVENREAVLKDHTKIRALVRAHSEKDQPPFGDSDDSVE
ADKSSPGIHLERSQASTTVDINTQVEKEVPPGSAIIHIKKHQVSVEGTNQ
TDVKAVGGPAKLLVVSLEEAWPLHGDCETDAEEGTSLTASVVADVRKSQL
PAEGDAGAEWAAAVLKQERAHEVGAQGGPPVAQVEQDLPISRENLTDLVV
DTDTLGESTQPQREGAQVPTGREREQHVGGTKDSEDNYGDSEDLDLQATQ
CFLENQGLEAVQSMEDEPTQAFMLTPPQELGPSHCSFQTTGTLDEPWEVL
ATQPFCLRESEDSETQPFDTHLEAYGPCLSPPRAIPGDQHPESPVHTEPM
GIQGRGRQTVDKVMGIPKETAERVGPERGPLERETEKLLPERQTDVTGEE
ELTKGKQDREQKQLLARDTQRQESDKNGESASPERDRESLKVEIETSEEI
QEKQVQKQTLPSKAFEREVERPVANRECDPAELEEKVPKVILERDTQRGE
PEGGSQDQKGQASSPTPEPGVGAGDLPGPTSAPVPSGSQSGGRGSPVSPR
RHQKGLLNCKMPPAEKASRIRAAEKVSRGDQESPDACLPPTVPEAPAPPQ
KPLNSQSQKHLAPPPLLSPLLPSIKPTVRKTRQDGSQEAPEAPLSSELEP
FHPKPKIRTRKSSRMTPFPATSAAPEPHPSTSTAQPVTPKPTSQATRSRT
NRSSVKTPEPVVPTAPELQPSTSTDQPVTSEPTSQVTRGRKSRSSVKTPE
TVVPTALELQPSTSTDRPVTSEPTSQATRGRKNRSSVKTPEPVVPTAPEL
QPSTSTDQPVTSEPTYQATRGRKNRSSVKTPEPVVPTAPELRPSTSTDRP
VTPKPTSRTTRSRTNMSSVKTPETVVPTAPELQISTSTDQPVTPKPTSRT
TRSRTNMSSVKNPESTVPIAPELPPSTSTEQPVTPEPTSRATRGRKNRSS
GKTPETLVPTAPKLEPSTSTDQPVTPEPTSQATRGRTNRSSVKTPETVVP
TAPELQPSTSTDQPVTPEPTSQATRGRTDRSSVKTPETVVPTAPELQASA
STDQPVTSEPTSRTTRGRKNRSSVKTPETVVPAAPELQPSTSTDQPVTPE
PTSRATRGRTNRSSVKTPESIVPIAPELQPSTSRNQLVTPEPTSRATRCR
TNRSSVKTPEPVVPTAPEPHPTTSTDQPVTPKLTSRATRRKTNRSSVKTP
KPVEPAASDLEPFTPTDQSVTPEAIAQGGQSKTLRSSTVRAMPVPTTPEF
QSPVTTDQPISPEPITQPSCIKRQRAAGNPGSLAAPIDHKPCSAPLEPKS
QASRNQRWGAVRAAESLTAIPEPASPQLLETPIHASQIQKVEPAGRSRFT
PELQPKASQSRKRSLATMDSPPHQKQPQRGEVSQKTVIIKEEEEDTAEKP
GKEEDVVTPKPGKRKRDQAEEEPNRIPSRSLRRTKLNQESTAPKVLFTGV
VDARGERAVLALGGSLAGSAAEASHLVTDRIRRTVKFLCALGRGIPILSL
DWLHQSRKAGFFLPPDEYVVTDPEQEKNFGFSLQDALSRARERRLLEGYE
IYVTPGVQPPPPQMGEIISCCGGTYLPSMPRSYKPQRVVITCPQDFPHCS
IPLRVGLPLLSPEFLLTGVLKQEAKPEAFVLSPLEMSST

MDC1 (Homo sapiens) is able to recognize following damages:
MDC1 (Homo sapiens) belongs to following protein families:
References:

Title Authors Journal
Prediction of the coding sequences of unidentified human genes. V. The coding sequences of 40 new genes (KIAA0161-KIAA0200) deduced by analysis of cDNA clones from human cell line KG-1. Nagase T, Seki N, Ishikawa K, Tanaka A, Nomura N DNA Res Jan. 1, 1996
NFBD1, a novel nuclear protein with signature motifs of FHA and BRCT, and an internal 41-amino acid repeat sequence, is an early participant in DNA damage response. Shang YL, Bodero AJ, Chen PL J Biol Chem Jan. 21, 2003
MDC1 is a mediator of the mammalian DNA damage checkpoint. Stewart GS, Wang B, Bignell CR, Taylor AM, Elledge SJ Nature Jan. 27, 2003
MDC1 is required for the intra-S-phase DNA damage checkpoint. Goldberg M, Stucki M, Falck J, D'Amours D, Rahman D, Pappin D, Bartek J, Jackson SP Nature Jan. 27, 2003
MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways. Lou Z, Minter-Dykhouse K, Wu X, Chen J Nature Jan. 27, 2003
NFBD1/KIAA0170 is a chromatin-associated protein involved in DNA damage signaling pathways. Xu X, Stern DF J Biol Chem March 7, 2003
NFBD1, like 53BP1, is an early and redundant transducer mediating Chk2 phosphorylation in response to DNA damage. Peng A, Chen PL J Biol Chem March 14, 2003
Mediator of DNA damage checkpoint protein 1 regulates BRCA1 localization and phosphorylation in DNA damage checkpoint control. Lou Z, Chini CC, Minter-Dykhouse K, Chen J J Biol Chem April 18, 2003
The DNA sequence and analysis of human chromosome 6. Mungall AJ, Palmer SA, Sims SK, Edwards CA, Ashurst JL, Wilming L, Jones MC, Horton R, Hunt SE, Scott CE, Gilbert JG, Clamp ME, Bethel G, Milne S, Ainscough R, Almeida JP, Ambrose KD, Andrews TD, Ashwell RI, Babbage AK, Bagguley CL, Bailey J, Banerjee R, Barker DJ, Barlow KF, Bates K, Beare DM, Beasley H, Beasley O, Bird CP, Blakey S, Bray-Allen S, Brook J, Brown AJ, Brown JY, Burford DC, Burrill W, Burton J, Carder C, Carter NP, Chapman JC, Clark SY, Clark G, Clee CM, Clegg S, Cobley V, Collier RE, Collins JE, Colman LK, Corby NR, Coville GJ, Culley KM, Dhami P, Davies J, Dunn M, Earthrowl ME, Ellington AE, Evans KA, Faulkner L, Francis MD, Frankish A, Frankland J, French L, Garner P, Garnett J, Ghori MJ, Gilby LM, Gillson CJ, Glithero RJ, Grafham DV, Grant M, Gribble S, Griffiths C, Griffiths M, Hall R, Halls KS, Hammond S, Harley JL, Hart EA, Heath PD, Heathcott R, Holmes SJ, Howden PJ, Howe KL, Howell GR, Huckle E, Humphray SJ, Humphries MD, Hunt AR, Johnson CM, Joy AA, Kay M, Keenan SJ, Kimberley AM, King A, Laird GK, Langford C, Lawlor S, Leongamornlert DA, Leversha M, Lloyd CR, Lloyd DM, Loveland JE, Lovell J, Martin S, Mashreghi-Mohammadi M, Maslen GL, Matthews L, McCann OT, McLaren SJ, McLay K, McMurray A, Moore MJ, Mullikin JC, Niblett D, Nickerson T, Novik KL, Oliver K, Overton-Larty EK, Parker A, Patel R, Pearce AV, Peck AI, Phillimore B, Phillips S, Plumb RW, Porter KM, Ramsey Y, Ranby SA, Rice CM, Ross MT, Searle SM, Sehra HK, Sheridan E, Skuce CD, Smith S, Smith M, Spraggon L, Squares SL, Steward CA, Sycamore N, Tamlyn-Hall G, Tester J, Theaker AJ, Thomas DW, Thorpe A, Tracey A, Tromans A, Tubby B, Wall M, Wallis JM, West AP, White SS, Whitehead SL, Whittaker H, Wild A, Willey DJ, Wilmer TE, Wood JM, Wray PW, Wyatt JC, Young L, Younger RM, Bentley DR, Coulson A, Durbin R, Hubbard T, Sulston JE, Dunham I, Rogers J, Beck S Nature Oct. 23, 2003
53BP1 and NFBD1/MDC1-Nbs1 function in parallel interacting pathways activating ataxia-telangiectasia mutated (ATM) in response to DNA damage. Mochan TA, Venere M, DiTullio RA Jr, Halazonetis TD Cancer Res Dec. 15, 2003
MDC1/NFBD1: a key regulator of the DNA damage response in higher eukaryotes. Stucki M, Jackson SP DNA Repair (Amst) Jan. 1, 2004
Mdc1 couples DNA double-strand break recognition by Nbs1 with its H2AX-dependent chromatin retention. Lukas C, Melander F, Stucki M, Falck J, Bekker-Jensen S, Goldberg M, Lerenthal Y, Jackson SP, Bartek J, Lukas J EMBO J July 7, 2004
Large-scale characterization of HeLa cell nuclear phosphoproteins. Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villen J, Li J, Cohn MA, Cantley LC, Gygi SP Proc Natl Acad Sci U S A Aug. 17, 2004
The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J Genome Res Oct. 1, 2004
MDC1 regulates DNA-PK autophosphorylation in response to DNA damage. Lou Z, Chen BP, Asaithamby A, Minter-Dykhouse K, Chen DJ, Chen J J Biol Chem Nov. 5, 2004
Structure of the BRCT repeat domain of MDC1 and its specificity for the free COOH-terminal end of the gamma-H2AX histone tail. Lee MS, Edwards RA, Thede GL, Glover JN J Biol Chem Sept. 16, 2005
MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks. Stucki M, Clapperton JA, Mohammad D, Yaffe MB, Smerdon SJ, Jackson SP Cell Dec. 1, 2005
Rapid evolution of major histocompatibility complex class I genes in primates generates new disease alleles in humans via hitchhiking diversity. Shiina T, Ota M, Shimizu S, Katsuyama Y, Hashimoto N, Takasu M, Anzai T, Kulski JK, Kikkawa E, Naruse T, Kimura N, Yanagiya K, Watanabe A, Hosomichi K, Kohara S, Iwamoto C, Umehara Y, Meyer A, Wanner V, Sano K, Macquin C, Ikeo K, Tokunaga K, Gojobori T, Inoko H, Bahram S Genetics July 1, 2006
Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M Cell Nov. 3, 2006
The full-ORF clone resource of the German cDNA Consortium. Bechtel S, Rosenfelder H, Duda A, Schmidt CP, Ernst U, Wellenreuther R, Mehrle A, Schuster C, Bahr A, Blocker H, Heubner D, Hoerlein A, Michel G, Wedler H, Kohrer K, Ottenwalder B, Poustka A, Wiemann S, Schupp I BMC Genomics Jan. 1, 2007
Global proteomic profiling of phosphopeptides using electron transfer dissociation tandem mass spectrometry. Molina H, Horn DM, Tang N, Mathivanan S, Pandey A Proc Natl Acad Sci U S A Jan. 13, 2007
ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER 3rd, Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Lerenthal Y, Shiloh Y, Gygi SP, Elledge SJ Science May 25, 2007
Improved titanium dioxide enrichment of phosphopeptides from HeLa cells and high confident phosphopeptide identification by cross-validation of MS/MS and MS/MS/MS spectra. Yu LR, Zhu Z, Chan KC, Issaq HJ, Dimitrov DS, Veenstra TD J Proteome Res Nov. 1, 2007
Quantitative phosphoproteome profiling of Wnt3a-mediated signaling network: indicating the involvement of ribonucleoside-diphosphate reductase M2 subunit phosphorylation at residue serine 20 in canonical Wnt signal transduction. Tang LY, Deng N, Wang LS, Dai J, Wang ZL, Jiang XS, Li SJ, Li L, Sheng QH, Wu DQ, Li L, Zeng R Mol Cell Proteomics Nov. 1, 2007
Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase. Kolas NK, Chapman JR, Nakada S, Ylanko J, Chahwan R, Sweeney FD, Panier S, Mendez M, Wildenhain J, Thomson TM, Pelletier L, Jackson SP, Durocher D Science Dec. 7, 2007
Automated phosphoproteome analysis for cultured cancer cells by two-dimensional nanoLC-MS using a calcined titania/C18 biphasic column. Imami K, Sugiyama N, Kyono Y, Tomita M, Ishihama Y Anal Sci Feb. 1, 2008
Cep164 is a mediator protein required for the maintenance of genomic stability through modulation of MDC1, RPA, and CHK1. Sivasubramaniam S, Sun X, Pan YR, Wang S, Lee EY Genes Dev March 1, 2008
Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient phosphoproteomic analysis. Cantin GT, Yi W, Lu B, Park SK, Xu T, Lee JD, Yates JR 3rd J Proteome Res March 1, 2008
A quantitative atlas of mitotic phosphorylation. Dephoure N, Zhou C, Villen J, Beausoleil SA, Bakalarski CE, Elledge SJ, Gygi SP Proc Natl Acad Sci U S A Aug. 5, 2008
Evaluation of the low-specificity protease elastase for large-scale phosphoproteome analysis. Wang B, Malik R, Nigg EA, Korner R Anal Chem Dec. 15, 2008
Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions. Mayya V, Lundgren DH, Hwang SI, Rezaul K, Wu L, Eng JK, Rodionov V, Han DK Sci Signal Jan. 1, 2009
Lysine acetylation targets protein complexes and co-regulates major cellular functions. Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M Science Aug. 14, 2009


Last modification of this entry: Oct. 13, 2010.

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