Regulation of repair choice: Cdk1 suppresses recruitment of end joining factors at DNA breaks.
Cell cycle plays a crucial role in regulating the pathway used to repair DNA double-strand breaks (DSBs). In Saccharomyces cerevisiae, homologous recombination is primarily limited to non-G(1) cells as the formation of recombinogenic single-stranded DNA requires CDK1-dependent 5' to 3' resection of DNA ends. However, the effect of cell cycle on non-homologous end joining (NHEJ) is not yet clearly defined. Using an assay to quantitatively measure the contributions of each repair pathway to repair product formation and cellular survival after DSB induction, we found that NHEJ is most efficient at G(1), and markedly repressed at G(2). Repression of NHEJ at G(2) is achieved by efficient end resection and by the reduced association of core NHEJ proteins with DNA breaks, both of which depend on the CDK1 activity. Importantly, repression of 5' end resection by CDK1 inhibition at G(2) alone did not fully restore either physical association of Ku/Dnl4-Lif1 with DSBs or NHEJ proficiency to the level at G(1). Expression of excess Ku can partially offset the inhibition of end joining at G(2). The results suggest that regulation of Ku/Dnl4-Lif1 affinity for DNA ends may contribute to the cell cycle-dependent modulation of NHEJ efficiency.
Zhang
Yu
Y
Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center at San Antonio, 78245, United States.
Shim
Eun Yong
EY
Davis
Melody
M
Lee
Sang Eun
SE
D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002453:Cell Cycle; D002470:Cell Survival; D053903:DNA Breaks, Double-Stranded; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000378:metabolism; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D011995:Recombination, Genetic; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000201:enzymology* / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism
D004268:DNA-Binding Proteins; C114091:LIF1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C081647:high affinity DNA-binding factor, S cerevisiae; D016203:CDC2 Protein Kinase; D011088:DNA Ligases; D045643:DNA Repair Enzymes; D000072481:DNA Ligase ATP
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