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  • The EMBO Journal (2003) 22, 6610 - 6620
  • doi:10.1093/emboj/cdg630

The Mre11 complex is required for ATM activation and the G2/M checkpoint

Christian T. Carson1,2, Rachel A. Schwartz1,2, Travis H. Stracker1,2,3, Caroline E. Lilley1, Darwin V. Lee1 and Matthew D. Weitzman1

  1. Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
  2. Graduate Program, Department of Biology, University of California, San Diego, CA 92093, USA
  3. Present address: Memorial Sloan Kettering Cancer Center, New York, NY, USA

Correspondence to:

Matthew D. Weitzman, E-mail: weitzman@salk.edu

Received 25 August 2003; Accepted 27 October 2003; Revised 24 October 2003

The maintenance of genome integrity requires a rapid and specific response to many types of DNA damage. The conserved and related PI3-like protein kinases, ataxia-telangiectasia mutated (ATM) and ATM-Rad3-related (ATR), orchestrate signal transduction pathways in response to genomic insults, such as DNA double-strand breaks (DSBs). It is unclear which proteins recognize DSBs and activate these pathways, but the Mre11/Rad50/NBS1 complex has been suggested to act as a damage sensor. Here we show that infection with an adenovirus lacking the E4 region also induces a cellular DNA damage response, with activation of ATM and ATR. Wild-type virus blocks this signaling through degradation of the Mre11 complex by the viral E1b55K/E4orf6 proteins. Using these viral proteins, we show that the Mre11 complex is required for both ATM activation and the ATM-dependent G2/M checkpoint in response to DSBs. These results demonstrate that the Mre11 complex can function as a damage sensor upstream of ATM/ATR signaling in mammalian cells.

  • Keywords:

    • adenovirus,
    • ATM,
    • ATR,
    • DNA double-strand breaks,
    • Mre11 complex