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

Nat Struct Mol Biol. 2012 Aug;19(8):803-10. doi: 10.1038/nsmb.2314. Epub 2012 Jul 8.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Apoptosis
  • Carrier Proteins / metabolism
  • Cell Line, Tumor
  • Cell Survival
  • Chromatin / metabolism
  • DNA Breaks, Double-Stranded
  • HIV / genetics
  • HeLa Cells
  • Humans
  • Nuclear Proteins / metabolism
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Recombinational DNA Repair / physiology*
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Virus Integration

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Chromatin
  • Nuclear Proteins
  • PSIP1 protein, human
  • RNA, Small Interfering
  • Transcription Factors
  • RBBP8 protein, human