Cell cycle- and DNA repair pathway-specific effects of apoptosis on tumor suppression.
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(-/-)p53(R172P/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 p53(R172P/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 p53(R172P/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.
Molecular Biology Program, Sloan-Kettering Institute, New York, NY 10021, USA.
Steven S
SS
Foster
Saurav
S
De
Linda K
LK
Johnson
John H J
JH
Petrini
Travis H
TH
Stracker
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D004249:DNA Damage; D004260:DNA Repair; D016158:Genes, p53; D051379:Mice; D009154:Mutation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology*