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An essential role for CtIP in chromosomal translocation formation through an alternative end-joining pathway

Nature Structural & Molecular Biology volume 18, pages 80–84 (2011)Cite this article

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Abstract

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.

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Figure 1: CtIP is essential for efficient chromosomal translocation formation by microhomology-prone alt-NHEJ.
Figure 2: In Ku70−/− cells, CtIP is essential for efficient chromosomal translocation formation but does not affect microhomology at breakpoint junctions.
Figure 3: Model for pathways involved in chromosomal translocations.

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Acknowledgements

We thank J. Chaudhuri and colleagues (Memorial Sloan-Kettering Cancer Center) for sharing unpublished results, R. Baer (Columbia University) for reagents, and E. Brunet, D. Simsek, P. Sung and other members of the Jasin laboratory for helpful discussions. This work was supported by a Leukemia and Lymphoma Society fellowship (Y.Z.), a Dorothy Rodbell Cohen Cancer Research Program Grant and US National Institutes of Health grant R01 NIHGM54668 (M.J.).

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  1. Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Yu Zhang & Maria Jasin

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  1. Yu Zhang
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Y.Z. performed the experiments. Y.Z. and M.J. designed the research and wrote the paper.

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Correspondence to Maria Jasin.

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Zhang, Y., Jasin, M. An essential role for CtIP in chromosomal translocation formation through an alternative end-joining pathway. Nat Struct Mol Biol 18, 80–84 (2011). https://doi.org/10.1038/nsmb.1940

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