An essential role for CtIP in chromosomal translocation formation through an alternative end-joining pathway.
Chromosomal translocations arise from the misjoining of DNA breaks, but the identity of the DNA repair factors and activities involved in their formation has been elusive. Here we show that depletion of CtIP, a DNA end-resection factor, results in a substantial decrease in chromosomal translocation frequency in mouse cells. Moreover, microhomology usage, a signature of the alternative nonhomologous end-joining pathway (alt-NHEJ), is significantly lower in translocation breakpoint junctions recovered from CtIP-depleted cells than in those from wild-type cells. Thus, we directly demonstrate that CtIP-mediated alt-NHEJ has a primary role in translocation formation. CtIP depletion in Ku70(-/-) cells reduces translocation frequency without affecting microhomology, indicating that Ku70-dependent NHEJ generates a fraction of translocations in wild-type cells. Translocations from both wild-type and Ku70(-/-) cells have smaller deletions on the participating chromosomes when CtIP is depleted, implicating the end-resection activity of CtIP in translocation formation.
Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Yu
Y
Zhang
Maria
M
Jasin
D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics; D055785:Gene Knockdown Techniques; D000072200:Ku Autoantigen; D051379:Mice; D008957:Models, Genetic; D017422:Sequence Analysis, DNA; D012689:Sequence Homology, Nucleic Acid; D014178:Translocation, Genetic / Q000502:physiology*
D034961:Antigens, Nuclear; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004247:DNA; D004268:DNA-Binding Proteins; D000072200:Ku Autoantigen; C501070:RBBP8 protein, mouse; C000606510:Xrcc6 protein, mouse