2AZM

Crystal structure of the MDC1 brct repeat in complex with the histone tail of gamma-H2AX

Summary for 2AZM

• Entry DOI: 10.2210/pdb2azm/pdb
• Descriptor: Mediator of DNA damage checkpoint protein 1, GAMMA-H2AX HISTONE (3 entities in total)
• Functional Keywords: brct repeat, protein-phosphopeptide complex, dna damage, cell cycle
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: Q14676
• Total number of polymer chains: 4
• Total formula weight: 48240.40

Authors

Clapperton, J.A.,Stucki, M.,Mohammad, D.,Yaffe, M.B.,Jackson, S.P.,Smerdon, S.J. (deposition date: 2005-09-12, release date: 2006-01-31, Last modification date: 2024-10-23)

Primary citation

Stucki, M.,Clapperton, J.A.,Mohammad, D.,Yaffe, M.B.,Smerdon, S.J.,Jackson, S.P.
MDC1 Directly Binds Phosphorylated Histone H2AX to Regulate Cellular Responses to DNA Double-Strand Breaks
Cell(Cambridge,Mass.), 123:1213-1226, 2005

PubMed Abstract: 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.

PubMed: 16377563
DOI: 10.1016/j.cell.2005.09.038

Experimental method

X-RAY DIFFRACTION (2.41 Å)