MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals

Zhenkun Lou, Katherine Minter-Dykhouse, Sonia Franco, Monica Gostissa, Melissa A. Rivera, Arkady Celeste, John P. Manis, Jan Van Deursen, André Nussenzweig, Tanya T. Paull, Frederick W. Alt, Junjie Chen

Research output: Contribution to journalArticle

438 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)187-200
Number of pages14
JournalMolecular Cell
Volume21
Issue number2
DOIs
StatePublished - Jan 20 2006

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Lou, Z., Minter-Dykhouse, K., Franco, S., Gostissa, M., Rivera, M. A., Celeste, A., Manis, J. P., Van Deursen, J., Nussenzweig, A., Paull, T. T., Alt, F. W., & Chen, J. (2006). MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals. Molecular Cell, 21(2), 187-200. https://doi.org/10.1016/j.molcel.2005.11.025