The DNA damage response comprises DNA repair, cell-cycle checkpoint control, and DNA damage-induced apoptosis that collectively promote genomic integrity and suppress tumorigenesis. Previously, we have shown that the Chk2 kinase functions independently of the Mre11 complex (Mre11, Rad50, and Nbs1) and ATM in apoptosis and suppresses tumorigenesis resulting from hypomorphic alleles of Mre11 or Nbs1. Based on this work, we have proposed that Chk2 limits the oncogenic potential of replication-associated DNA damage. Here we further address the role of Chk2 and damage-induced apoptosis in suppressing the oncogenic potential of chromosome breaks. We show that loss of Chk2 or a mutation in p53 (R172P), which selectively impairs its function in apoptosis, rescued the lethality of mice lacking Lig4, a ligase required for nonhomologous end-joining (NHEJ) repair of DNA double-strand breaks in G0/G1. In contrast to Lig4−/−p53−/− mice, Lig4−/−Chk2−/− and Lig4−/−p53R172P/R172P mice were not prone to organ-specific, rapid tumorigenesis. Although the severe NHEJ deficiency of Lig4−/− was a less potent initiator of tumorigenesis in the p53R172P/R172P and Chk2−/− backgrounds, where p53 cell-cycle functions are largely intact, even mild defects in the intra-S and G2/M checkpoints caused by mutations in Nbs1 are sufficient to influence malignancy in p53R172P/R172P mice. We conclude that the oncogenic potential of double-strand breaks resulting from NHEJ deficiency is highly restricted by nonapoptotic functions of p53, such as the G1/S checkpoint or senescence, suggesting that the particular facets of the DNA damage response required for tumor suppression are dictated by the proliferative status of the tumor-initiating cell.
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Publication status||Published - 19 Jun 2012|
Bibliographical noteFreely available online through the PNAS open access option.
- Chromosome instability
- Kinase signalling
- Tumour suppressor
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)