Hepatoma-derived growth factor-related protein 2 promotes DNA repair by homologous recombination

Nucleic Acids Res. 2016 Mar 18;44(5):2214-26. doi: 10.1093/nar/gkv1526. Epub 2015 Dec 31.

Abstract

We have recently identified lens epithelium-derived growth factor (LEDGF/p75, also known as PSIP1) as a component of the homologous recombination DNA repair machinery. Through its Pro-Trp-Trp-Pro (PWWP) domain, LEDGF/p75 binds to histone marks associated with active transcription and promotes DNA end resection by recruiting DNA endonuclease retinoblastoma-binding protein 8 (RBBP8/CtIP) to broken DNA ends. Here we show that the structurally related PWWP domain-containing protein, hepatoma-derived growth factor-related protein 2 (HDGFRP2), serves a similar function in homologous recombination repair. Its depletion compromises the survival of human U2OS osteosarcoma and HeLa cervix carcinoma cells and impairs the DNA damage-induced phosphorylation of replication protein A2 (RPA2) and the recruitment of DNA endonuclease RBBP8/CtIP to DNA double strand breaks. In contrast to LEDGF/p75, HDGFRP2 binds preferentially to histone marks characteristic for transcriptionally silent chromatin. Accordingly, HDGFRP2 is found in complex with the heterochromatin-binding chromobox homologue 1 (CBX1) and Pogo transposable element with ZNF domain (POGZ). Supporting the functionality of this complex, POGZ-depleted cells show a similar defect in DNA damage-induced RPA2 phosphorylation as HDGFRP2-depleted cells. These data suggest that HDGFRP2, possibly in complex with POGZ, recruits homologous recombination repair machinery to damaged silent genes or to active genes silenced upon DNA damage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Binding Sites
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Line, Tumor
  • Cell Survival
  • Chromatin / chemistry
  • Chromatin / metabolism
  • Chromobox Protein Homolog 5
  • Chromosomal Proteins, Non-Histone / genetics*
  • Chromosomal Proteins, Non-Histone / metabolism
  • DNA Breaks, Double-Stranded*
  • Endodeoxyribonucleases
  • HeLa Cells
  • Histones / genetics*
  • Histones / metabolism
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Osteoblasts / metabolism
  • Osteoblasts / pathology
  • Phosphorylation
  • Protein Binding
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Recombinational DNA Repair*
  • Replication Protein A / genetics
  • Replication Protein A / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transposases / antagonists & inhibitors
  • Transposases / genetics*
  • Transposases / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • CBX1 protein, human
  • Carrier Proteins
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • Histones
  • Intercellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • POGZ protein, human
  • PSIP1 protein, human
  • RNA, Small Interfering
  • Replication Protein A
  • Transcription Factors
  • hepatoma-derived growth factor
  • Chromobox Protein Homolog 5
  • Transposases
  • RPA2 protein, human
  • Endodeoxyribonucleases
  • RBBP8 protein, human