Chk2 suppresses the oncogenic potential of DNA replication-associated DNA damage Journal Article

Authors: Stracker, T. H.; Couto, S. S.; Cordon-Cardo, C.; Matos, T.; Petrini, J. H. J.
Article Title: Chk2 suppresses the oncogenic potential of DNA replication-associated DNA damage
Abstract: The Mre11 complex (Mre11, Rad50, and Nbs1) and Chk2 have been implicated in the DNA-damage response, an inducible process required for the suppression of malignancy. The Mre11 complex is predominantly required for repair and checkpoint activation in S phase, whereas Chk2 governs apoptosis. We examined the relationship between the Mre11 complex and Chk2 in the DNA-damage response via the establishment of Nbs1ΔB/ΔB Chk2-/- and Mre11ATLD1/ATLD1 Chk2-/- mice. Chk2 deficiency did not modify the checkpoint defects or chromosomal instability of Mre11 complex mutants; however, the double-mutant mice exhibited synergistic defects in DNA-damage-induced p53 regulation and apoptosis. Nbs1ΔB/ΔB Chk2-/- and Mre11ATLD1/ATLD1 Chk2-/- mice were also predisposed to tumors. In contrast, DNA-PKcs-deficient mice, in which G1-specific chromosome breaks are present, did not exhibit synergy with Chk2-/- mutants. These data suggest that Chk2 suppresses the oncogenic potential of DNA damage arising during S and G2 phases of the cell cycle. © 2008 Elsevier Inc. All rights reserved.
Keywords: controlled study; mutation; dna-binding proteins; exons; nonhuman; mutant protein; dna replication; animal cell; mouse; animals; cell cycle proteins; mice; mre11 protein; rad50 protein; animal tissue; dna damage; mus; cell cycle; cell cycle s phase; complex formation; dna repair; apoptosis; enzyme inhibition; signaling; alleles; transcription, genetic; protein p53; nibrin; nuclear proteins; cancer inhibition; oncogene; dna; regulatory mechanism; protein-serine-threonine kinases; nucleotide sequence; fibroblast; dna repair enzymes; tumor suppressor protein p53; chromosomal instability; chromosome breakage; genome; cellcycle; checkpoint kinase 2; cell cycle g2 phase; cyclin-dependent kinase inhibitor p16; cell cycle g1 phase; enzyme mechanism; dna, complementary; enzyme deficiency; precancerous conditions; dna-activated protein kinase; embryo fibroblast
Journal Title: Molecular Cell
Volume: 31
Issue: 1
ISSN: 1097-2765
Publisher: Cell Press  
Date Published: 2008-07-11
Start Page: 21
End Page: 32
Language: English
DOI: 10.1016/j.molcel.2008.04.028
PUBMED: 18614044
PROVIDER: scopus
PMCID: PMC2586815
Notes: --- - "Cited By (since 1996): 20" - "Export Date: 17 November 2011" - "CODEN: MOCEF" - "Molecular Sequence Numbers: GENBANK: GSE11436;" - "Source: Scopus"
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MSK Authors
  1. Suzana S Couto
    11 Couto
  2. John Petrini
    76 Petrini
  3. Tulio A Matos
    2 Matos