| Structural highlights
Function
MDC1_HUMAN 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 and CHEK2 kinases, and stabilization of TP53 and apoptosis. ATM and CHEK2 may also be activated independently by a parallel pathway mediated by TP53BP1.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Histone variant H2AX phosphorylation in response to DNA damage is the major signal for recruitment of DNA-damage-response proteins to regions of damaged chromatin. Loss of H2AX causes radiosensitivity, genome instability, and DNA double-strand-break repair defects, yet the mechanisms underlying these phenotypes remain obscure. Here, we demonstrate that mammalian MDC1/NFBD1 directly binds to phospho-H2AX (gammaH2AX) by specifically interacting with the phosphoepitope at the gammaH2AX carboxyl terminus. Moreover, through a combination of biochemical, cell-biological, and X-ray crystallographic approaches, we reveal the molecular details of the MDC1/NFBD1-gammaH2AX complex. These data provide compelling evidence that the MDC1/NFBD1 BRCT repeat domain is the major mediator of gammaH2AX recognition following DNA damage. We further show that MDC1/NFBD1-gammaH2AX complex formation regulates H2AX phosphorylation and is required for normal radioresistance and efficient accumulation of DNA-damage-response proteins on damaged chromatin. Thus, binding of MDC1/NFBD1 to gammaH2AX plays a central role in the mammalian response to DNA damage.
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. 2005 Dec 29;123(7):1213-26. PMID:16377563[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Mochan TA, Venere M, DiTullio RA Jr, Halazonetis TD. 53BP1 and NFBD1/MDC1-Nbs1 function in parallel interacting pathways activating ataxia-telangiectasia mutated (ATM) in response to DNA damage. Cancer Res. 2003 Dec 15;63(24):8586-91. PMID:14695167
- ↑ Shang YL, Bodero AJ, Chen PL. 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. J Biol Chem. 2003 Feb 21;278(8):6323-9. Epub 2002 Dec 9. PMID:12475977 doi:10.1074/jbc.M210749200
- ↑ Xu X, Stern DF. NFBD1/KIAA0170 is a chromatin-associated protein involved in DNA damage signaling pathways. J Biol Chem. 2003 Mar 7;278(10):8795-803. Epub 2002 Dec 23. PMID:12499369 doi:10.1074/jbc.M211392200
- ↑ Peng A, Chen PL. NFBD1, like 53BP1, is an early and redundant transducer mediating Chk2 phosphorylation in response to DNA damage. J Biol Chem. 2003 Mar 14;278(11):8873-6. Epub 2003 Jan 24. PMID:12551934 doi:10.1074/jbc.C300001200
- ↑ Lou Z, Chini CC, Minter-Dykhouse K, Chen J. Mediator of DNA damage checkpoint protein 1 regulates BRCA1 localization and phosphorylation in DNA damage checkpoint control. J Biol Chem. 2003 Apr 18;278(16):13599-602. Epub 2003 Feb 27. PMID:12611903 doi:10.1074/jbc.C300060200
- ↑ Goldberg M, Stucki M, Falck J, D'Amours D, Rahman D, Pappin D, Bartek J, Jackson SP. MDC1 is required for the intra-S-phase DNA damage checkpoint. Nature. 2003 Feb 27;421(6926):952-6. PMID:12607003 doi:10.1038/nature01445
- ↑ Lou Z, Minter-Dykhouse K, Wu X, Chen J. MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways. Nature. 2003 Feb 27;421(6926):957-61. PMID:12607004 doi:10.1038/nature01447
- ↑ Stewart GS, Wang B, Bignell CR, Taylor AM, Elledge SJ. MDC1 is a mediator of the mammalian DNA damage checkpoint. Nature. 2003 Feb 27;421(6926):961-6. PMID:12607005 doi:10.1038/nature01446
- ↑ Lukas C, Melander F, Stucki M, Falck J, Bekker-Jensen S, Goldberg M, Lerenthal Y, Jackson SP, Bartek J, Lukas J. Mdc1 couples DNA double-strand break recognition by Nbs1 with its H2AX-dependent chromatin retention. EMBO J. 2004 Jul 7;23(13):2674-83. Epub 2004 Jun 17. PMID:15201865 doi:10.1038/sj.emboj.7600269
- ↑ Lou Z, Chen BP, Asaithamby A, Minter-Dykhouse K, Chen DJ, Chen J. MDC1 regulates DNA-PK autophosphorylation in response to DNA damage. J Biol Chem. 2004 Nov 5;279(45):46359-62. Epub 2004 Sep 17. PMID:15377652 doi:10.1074/jbc.C400375200
- ↑ Stucki M, Clapperton JA, Mohammad D, Yaffe MB, Smerdon SJ, Jackson SP. MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks. Cell. 2005 Dec 29;123(7):1213-26. PMID:16377563 doi:10.1016/j.cell.2005.09.038
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