Collaboration of homologous recombination and nonhomologous end-joining factors for the survival and integrity of mice and cells Journal Article

Authors: Couedel, C.; Mills, K. D.; Barchi, M.; Shen, L.; Olshen, A.; Johnson, R. D.; Nussenzweig, A.; Essers, J.; Kanaar, R.; Li, G. C.; Alt, F. W.; Jasin, M.
Article Title: Collaboration of homologous recombination and nonhomologous end-joining factors for the survival and integrity of mice and cells
Abstract: Homologous recombination (HR) and nonhomologous end-joining (NHEJ) are mechanistically distinct DNA repair pathways that contribute substantially to double-strand break (DSB) repair in mammalian cells. We have combined mutations in factors from both repair pathways, the HR protein Rad54 and the DNA-end-binding factor Ku80, which has a role in NHEJ. Rad54 -/-Ku80-/- mice were severely compromised in their survival, such that fewer double mutants were born than expected, and only a small proportion of those born reached adulthood. However, double-mutant mice died at lower frequency from tumors than Ku80 single mutant mice, likely as a result of rapid demise at a young age from other causes. When challenged with an exogenous DNA damaging agent, ionizing radiation, double-mutant mice were exquisitely sensitive to low doses. Tissues and cells from double-mutant mice also showed indications of spontaneous DNA damage. Testes from some Rad54 -/-Ku80-/- mice displayed enhanced apoptosis and reduced sperm production, and embryonic fibroblasts from Rad54-/-Ku80 -/- animals accumulated foci of γ-H2AX, a marker for DSBs. The substantially increased DNA damage response in the double mutants implies a cooperation of the two DSB repair pathways for survival and genomic integrity in the animal.
Keywords: survival rate; unclassified drug; dna-binding proteins; nonhuman; animal cell; mouse; mammalia; animals; mice; dna damage; homologous recombination; cell survival; cells, cultured; dna repair; embryo; mice, mutant strains; protein; animalia; dna strand breakage; nuclear proteins; double stranded dna; genetic recombination; brain; recombination, genetic; fibroblast; fibroblasts; radiation, ionizing; rad54; rad54 protein; gamma irradiation; aging; animals, newborn; polydeoxyribonucleotide synthase; histones; testis; nonhomologous end-joining; antigens, nuclear; ku80; dna double-strand break; male; female; priority journal; article; dna end binding factor ku80; ku80 protein; nonhomologous end joining factor; fetal death
Journal Title: Genes and Development
Volume: 18
Issue: 11
ISSN: 0890-9369
Publisher: Cold Spring Harbor Laboratory Press  
Date Published: 2004-01-01
Start Page: 1293
End Page: 1304
Language: English
DOI: 10.1101/gad.1209204
PROVIDER: scopus
PMCID: PMC420355
PUBMED: 15175261
Notes: Genes Dev. -- Cited By (since 1996):96 -- Export Date: 16 June 2014 -- CODEN: GEDEE -- Source: Scopus
Citation Impact
MSK Authors
  1. Marco Barchi
    12 Barchi
  2. Gloria C Li
    131 Li
  3. Adam B Olshen
    107 Olshen
  4. Maria Jasin
    231 Jasin
  5. Ling-Bo Shen
    10 Shen