Figure 1.

The Mre11 complex and Chk2 in apoptosis and tumor suppression. (A) The Mre11 complex (MRN) functions at multiple stages in apoptotic signaling; the activation of ATM, which is impaired by the Mre11^ATLD1 allele, and the promotion of ATM activity by the C-terminal domain of Nbs1 that is deleted in the Nbs1^ΔC allele. ATM phosphorylates Chk2 and this requires the Mre11 complex, but Chk2 promotes apoptosis in the absence of ATM, defining a parallel pathway. ⁴,⁵ (B) The influence of the Mre11 complex and Chk2 on tumorigenesis. Alleles that impair the metabolism of DNA replication associated breaks in S and G₂ (Mre11^ATLD1, Nbs1^ΔB or Brca1^{Δ or Δ11}) predispose tumors in the absence of Chk2.⁵,²⁵,²⁶ DSBs arising from the deficient repair of programmed breaks, as in DNA-PKcs deficient mice (Prkdc^scid), are not sufficient to promote tumorigenesis in the absence of Chk2.⁵ The G₁/S and G₂/M checkpoints are indicated in red.