Details

Autor(en) / Beteiligte

• Stucki, Manuel
• Clapperton, Julie A.
• Mohammad, Duaa
• Yaffe, Michael B.
• Smerdon, Stephen J.
• Jackson, Stephen P.

Titel

MDC1 Directly Binds Phosphorylated Histone H2AX to Regulate Cellular Responses to DNA Double-Strand Breaks

Ist Teil von

• Cell, 2005-12, Vol.123 (7), p.1213-1226

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2005

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 (γH2AX) by specifically interacting with the phosphoepitope at the γH2AX carboxyl terminus. Moreover, through a combination of biochemical, cell-biological, and X-ray crystallographic approaches, we reveal the molecular details of the MDC1/NFBD1-γH2AX complex. These data provide compelling evidence that the MDC1/NFBD1 BRCT repeat domain is the major mediator of γH2AX recognition following DNA damage. We further show that MDC1/NFBD1-γH2AX 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 γH2AX plays a central role in the mammalian response to DNA damage.