TY - JOUR
T1 - MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals
AU - Lou, Zhenkun
AU - Minter-Dykhouse, Katherine
AU - Franco, Sonia
AU - Gostissa, Monica
AU - Rivera, Melissa A.
AU - Celeste, Arkady
AU - Manis, John P.
AU - Van Deursen, Jan
AU - Nussenzweig, André
AU - Paull, Tanya T.
AU - Alt, Frederick W.
AU - Chen, Junjie
N1 - Funding Information:
We thank Dr. John H.J. Petrini (Memorial Sloan Kettering Cancer Center) for providing anti-mouse NBS1 antibodies and Dr. Yosef Shiloh (Tel Aviv University) for providing anti-mouse ATM antibodies. We thank Jamie Wood for providing suggestions and proofreading of this manuscript. This work is supported by grants from National Institute of Health (NIH RO1 CA89239 and CA92312 to J.C.). J.C. is a recipient of DOD breast cancer career development award (DAMD17-02-1-0472). Z.L. is a recipient of DOD breast cancer fellowship award (DAMD17-03-1-0610).
PY - 2006/1/20
Y1 - 2006/1/20
N2 - MDC1 functions in checkpoint activation and DNA repair following DNA damage. To address the physiological role of MDC1, we disrupted the MDC1 gene in mice. MDC1-/- mice recapitulated many phenotypes of H2AX -/- mice, including growth retardation, male infertility, immune defects, chromosome instability, DNA repair defects, and radiation sensitivity. At the molecular level, H2AX, MDC1, and ATM form a positive feedback loop, with MDC1 directly mediating the interaction between H2AX and ATM. MDC1 binds phosphorylated H2AX through its BRCT domain and ATM through its FHA domain. Through these interactions, MDC1 accumulates activated ATM flanking the sites of DNA damage, facilitating further ATM-dependent phosphorylation of H2AX and the amplification of DNA damage signals. In the absence of MDC1, many downstream ATM signaling events are defective. These results suggest that MDC1, as a signal amplifier of the ATM pathway, is vital in controlling proper DNA damage response and maintaining genomic stability.
AB - MDC1 functions in checkpoint activation and DNA repair following DNA damage. To address the physiological role of MDC1, we disrupted the MDC1 gene in mice. MDC1-/- mice recapitulated many phenotypes of H2AX -/- mice, including growth retardation, male infertility, immune defects, chromosome instability, DNA repair defects, and radiation sensitivity. At the molecular level, H2AX, MDC1, and ATM form a positive feedback loop, with MDC1 directly mediating the interaction between H2AX and ATM. MDC1 binds phosphorylated H2AX through its BRCT domain and ATM through its FHA domain. Through these interactions, MDC1 accumulates activated ATM flanking the sites of DNA damage, facilitating further ATM-dependent phosphorylation of H2AX and the amplification of DNA damage signals. In the absence of MDC1, many downstream ATM signaling events are defective. These results suggest that MDC1, as a signal amplifier of the ATM pathway, is vital in controlling proper DNA damage response and maintaining genomic stability.
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U2 - 10.1016/j.molcel.2005.11.025
DO - 10.1016/j.molcel.2005.11.025
M3 - Article
C2 - 16427009
AN - SCOPUS:30744465308
SN - 1097-2765
VL - 21
SP - 187
EP - 200
JO - Molecular cell
JF - Molecular cell
IS - 2
ER -