Working together and apart: the twisted relationship of the Mre11 complex and Chk2 in apoptosis and tumor suppression

Abstract

Central to the DNA damage response (DDR) is the highly conserved Mre11 complex consisting of Mre11, Rad50 and Nbs1. The Mre11 complex acts as a sensor of DNA double-strand breaks (DSBs) and regulates the signal transduction cascades that are triggered following damage detection.(1) Rare human genetic instability syndromes such as Ataxia-telangiectasia (A-T) and Nijmegen Breakage Syndrome (NBS) have underscored the importance of the DSB response in the suppression of tumorigenesis, as well as other severe pathologies affecting the development of both the immune system and the central nervous system. Using murine models of the human diseases, we have investigated the role of the Mre11 complex, and other modulators of the DSB response, in tumor suppression.(2,3) We found that the checkpoint kinase Chk2 is crucial for the suppression of a diverse array of tumor types in Mre11 complex mutants and uncovered multiple roles for the Mre11 complex in apoptotic signaling in parallel to Chk2.(4,5).

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. , (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.,, 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. The G₁/S and G₂/M checkpoints are indicated in red.