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 |
| DOI/URL: | |
| Notes: | Genes Dev. -- Cited By (since 1996):96 -- Export Date: 16 June 2014 -- CODEN: GEDEE -- Source: Scopus |
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