Double strand break metabolism and cancer susceptibility: lessons from the mre11 complex.
Hypomorphic mutants affecting the Mre11 complex components Mre11 (Mre11(ATLD1/ATLD1)) and Nbs1 (Nbs1(DeltaB/DeltaB)) have been established in the mouse. These mutations recapitulate those inherited in human chromosome fragility syndromes, the ataxia-telangiectasia like disorder and Nijmegen breakage syndrome. At the cellular level, the human and murine mutants exhibit defects in the intra S and G2/M checkpoints and marked chromosome instability. Whereas these outcomes are associated with predisposition to malignancy in humans, similar predisposition was not observed in either Mre11(ATLD1/ATLD1) or Nbs1(DeltaB/DeltaB) mice. These data demonstrate that chromosome breakage per se is insufficient to significantly enhance the initiation of tumorigenesis. However, these mutations greatly enhanced the risk of malignancy in p53+/- mice. We propose that proper metabolism of chromosome breaks arising during DNA replication is uniquely important for suppressing loss of heterozygosity and thus the penetrance of recessive oncogenic lesions.
Petrini
John H J
JH
Molecular Biology Program, Memorial Sloan Kettering Cancer Center and Cornell University Graduate School of Medical Sciences, New York, New York 10021, USA. petrinij@mskcc.org
Theunissen
Jan-Willem F
JW
D000818:Animals; D001260:Ataxia Telangiectasia / Q000235:genetics; D002453:Cell Cycle / Q000502:physiology*; D004249:DNA Damage; D045643:DNA Repair Enzymes; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004198:Disease Susceptibility; D005838:Genotype; D006801:Humans; D000076228:MRE11 Homologue Protein; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C512689:Mre11a protein, mouse; D016159:Tumor Suppressor Protein p53; D000076228:MRE11 Homologue Protein; D045643:DNA Repair Enzymes