Abstract
Lens epithelium–derived growth factor p75 splice variant (LEDGF) is a chromatin-binding protein known for its antiapoptotic activity and ability to direct human immunodeficiency virus into active transcription units. Here we show that LEDGF promotes the repair of DNA double-strand breaks (DSBs) by the homologous recombination repair pathway. Depletion of LEDGF impairs the recruitment of C-terminal binding protein interacting protein (CtIP) to DNA DSBs and the subsequent CtIP-dependent DNA-end resection. LEDGF is constitutively associated with chromatin through its Pro-Trp-Trp-Pro (PWWP) domain that binds preferentially to epigenetic methyl-lysine histone markers characteristic of active transcription units. LEDGF binds CtIP in a DNA damage–dependent manner, thereby enhancing its tethering to the active chromatin and facilitating its access to DNA DSBs. These data highlight the role of PWWP-domain proteins in DNA repair and provide a molecular explanation for the antiapoptotic and cancer cell survival–activities of LEDGF.
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Acknowledgements
We thank A. Engelman (Dana-Farber Cancer Institute, Harvard Medical School) for providing us with Psip1-deficient cells, K.G. Henriksen for technical assistance and L. Vinner for discussions regarding HIV integration. This work was supported by the Danish Cancer Society and the Novo Nordisk Foundation (M.D., J.L., J.B. and M.J.), the Danish National Research Foundation and the John and Birthe Meyer Foundation (J.L., J.B. and M.J.), the Danish Medical Research Council, the Lundbeck Foundation and the European Commission FP7 (APO-SYS) (M.J.), and DDResponse, Biomedreg and INFLA-CARE (J.B).
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M.D. and M.J. designed the project and wrote the manuscript; M.D. and A.B. performed most of the experiments, supported by K.F., L.K.P., H.B., N.H.T.P. and M.R.; and C.S.S., C.L., J.L., J.B. and P.H.B.S. provided essential knowhow and support for the project and for preparing the manuscript.
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Daugaard, M., Baude, A., Fugger, K. et al. LEDGF (p75) promotes DNA-end resection and homologous recombination. Nat Struct Mol Biol 19, 803–810 (2012). https://doi.org/10.1038/nsmb.2314
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DOI: https://doi.org/10.1038/nsmb.2314
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