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

Mads Daugaard; Annika Baude; Kasper Fugger; Lou Klitgaard Povlsen; Halfdan Beck; Claus Storgaard Sørensen; Nikolaj H T Petersen; Poul H B Sorensen; Claudia Lukas; Jiri Bartek; Jiri Lukas; Mikkel Rohde; Marja Jaattela

doi:10.1038/nsmb.2314

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

Mads Daugaard, Annika Baude, Kasper Fugger, Lou Klitgaard Povlsen, Halfdan Beck, Claus Storgaard Sørensen, Nikolaj H T Petersen, Poul H B Sorensen, Claudia Lukas, Jiri Bartek, Jiri Lukas, Mikkel Rohde, Marja Jaattela

107 Citations (Scopus)

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.

Original language	English
Journal	Nature Structural & Molecular Biology
Volume	19
Issue number	8
Pages (from-to)	803-810
Number of pages	8
DOIs	https://doi.org/10.1038/nsmb.2314
Publication status	Published - Aug 2012

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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.",

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doi = "10.1038/nsmb.2314",

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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.

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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 -

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

Abstract

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