DNA-dependent protein kinase suppresses double-strand break-induced and spontaneous homologous recombination

Proceedings of the National Academy of Sciences of the United States of America
Chris AllenJac A Nickoloff

Abstract

DNA-dependent protein kinase (DNA-PK), composed of Ku70, Ku80, and the catalytic subunit (DNA-PKcs), is involved in repairing double-strand breaks (DSBs) by nonhomologous end-joining (NHEJ). Certain proteins involved in NHEJ are also involved in DSB repair by homologous recombination (HR). To test the effects of DNA-PKcs on DSB-induced HR, we integrated neo direct repeat HR substrates carrying the I-SceI recognition sequence into DNA-PKcs-defective Chinese hamster ovary (V3) cells. The DNA-PKcs defect was complemented with a human DNA-PKcs cDNA. DSB-induced HR frequencies were 1.5- to 3-fold lower with DNA-PKcs complementation. In complemented and uncomplemented strains, all products arose by gene conversion without associated crossover, and average conversion tract lengths were similar. Suppression of DSB-induced HR in complemented cells probably reflects restoration of NHEJ, consistent with competition between HR and NHEJ during DSB repair. Interestingly, spontaneous HR rates were 1.6- to >3.5-fold lower with DNA-PKcs complementation. DNA-PKcs may suppress spontaneous HR through NHEJ of spontaneous DSBs, perhaps at stalled or blocked replication forks. Because replication protein A (RPA) is involved in both replication and HR...Continue Reading

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Citations

Jun 5, 2004·DNA Repair·Susan M BaileyEdwin H Goodwin
Dec 25, 2007·Cell Research·Meena ShrivastavJac A Nickoloff
Feb 24, 2010·Nature Reviews. Molecular Cell Biology·Mary Ellen Moynahan, Maria Jasin
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Jun 26, 2007·Nature Structural & Molecular Biology·Yu ZhangAlan E Tomkinson
Nov 21, 2007·Nature Structural & Molecular Biology·Su WuYang Shi
Jun 20, 2008·Proceedings of the National Academy of Sciences of the United States of America·Farjana J FattahEric A Hendrickson
Feb 6, 2010·Proceedings of the National Academy of Sciences of the United States of America·Romain ChayotMiria Ricchetti
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Feb 1, 2011·Journal of Molecular Cell Biology·Chris AllenJac A Nickoloff
Oct 25, 2003·Nucleic Acids Research·Rosine Onclercq-DelicMounira Amor-Guéret
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