title: LEDGF (p75) promotes DNA-end resection and homologous recombination.
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.
authors: Cell Death and Metabolism, Danish Cancer Society Research Center, Copenhagen, Denmark.
authors: Mads
authors: M
authors: Daugaard
authors: Annika
authors: A
authors: Baude
authors: Kasper
authors: K
authors: Fugger
authors: Lou Klitgaard
authors: LK
authors: Povlsen
authors: Halfdan
authors: H
authors: Beck
authors: Claus Storgaard
authors: CS
authors: Sørensen
authors: Nikolaj H T
authors: NH
authors: Petersen
authors: Poul H B
authors: PH
authors: Sorensen
authors: Claudia
authors: C
authors: Lukas
authors: Jiri
authors: J
authors: Bartek
authors: Jiri
authors: J
authors: Lukas
authors: Mikkel
authors: M
authors: Rohde
authors: Marja
authors: M
authors: Jäättelä
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D002843:Chromatin / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004706:Endodeoxyribonucleases; D006678:HIV / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D059767:Recombinational DNA Repair / Q000502:physiology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016662:Virus Integration
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D002843:Chromatin; D009687:Nuclear Proteins; C504649:PSIP1 protein, human; D034741:RNA, Small Interfering; D014157:Transcription Factors; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human