LEDGF (p75) promotes DNA-end resection and homologous recombination

TY - JOUR

T1 - LEDGF (p75) promotes DNA-end resection and homologous recombination

AU - Daugaard, Mads

AU - Baude, Annika

AU - Fugger, Kasper

AU - Povlsen, Lou Klitgaard

AU - Beck, Halfdan

AU - Sørensen, Claus Storgaard

AU - Petersen, Nikolaj H T

AU - Sorensen, Poul H B

AU - Lukas, Claudia

AU - Bartek, Jiri

AU - Lukas, Jiri

AU - Rohde, Mikkel

AU - Jaattela, Marja

PY - 2012/8

Y1 - 2012/8

N2 - 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.

AB - 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.

U2 - 10.1038/nsmb.2314

DO - 10.1038/nsmb.2314

M3 - Journal article

C2 - 22773103

SN - 1545-9993

VL - 19

SP - 803

EP - 810

JO - Nature Structural and Molecular Biology

JF - Nature Structural and Molecular Biology

IS - 8

ER -