| 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]
Publication Abstract from PubMed
Mdc1 is a large modular phosphoprotein scaffold that maintains signaling and repair complexes at double-stranded DNA break sites. Mdc1 is anchored to damaged chromatin through interaction of its C-terminal BRCT-repeat domain with the tail of gammaH2AX following DNA damage, but the role of the N-terminal forkhead-associated (FHA) domain remains unclear. We show that a major binding target of the Mdc1 FHA domain is a previously unidentified DNA damage and ATM-dependent phosphorylation site near the N-terminus of Mdc1 itself. Binding to this motif stabilizes a weak self-association of the FHA domain to form a tight dimer. X-ray structures of free and complexed Mdc1 FHA domain reveal a 'head-to-tail' dimerization mechanism that is closely related to that seen in pre-activated forms of the Chk2 DNA damage kinase, and which both positively and negatively influences Mdc1 FHA domain-mediated interactions in human cells prior to and following DNA damage.
The molecular basis of ATM-dependent dimerization of the Mdc1 DNA damage checkpoint mediator.,Jungmichel S, Clapperton JA, Lloyd J, Hari FJ, Spycher C, Pavic L, Li J, Haire LF, Bonalli M, Larsen DH, Lukas C, Lukas J, MacMillan D, Nielsen ML, Stucki M, Smerdon SJ Nucleic Acids Res. 2012 May;40(9):3913-28. Epub 2012 Jan 10. PMID:22234878[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
- ↑ Jungmichel S, Clapperton JA, Lloyd J, Hari FJ, Spycher C, Pavic L, Li J, Haire LF, Bonalli M, Larsen DH, Lukas C, Lukas J, MacMillan D, Nielsen ML, Stucki M, Smerdon SJ. The molecular basis of ATM-dependent dimerization of the Mdc1 DNA damage checkpoint mediator. Nucleic Acids Res. 2012 May;40(9):3913-28. Epub 2012 Jan 10. PMID:22234878 doi:10.1093/nar/gkr1300
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