2. Academic Validation
  3. Hepatoma-derived growth factor-related protein 2 promotes DNA repair by homologous recombination

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.
Annika Baude 1,  Tania Løve Aaes 1,  Beibei Zhai 2,  Nader Al-Nakouzi 2,  Htoo Zarni Oo 2,  Mads Daugaard 2,  Mikkel Rohde 1,  Marja Jäättelä 3
Affiliations

Affiliations

  • 1 Unit of Cell Death and Metabolism, Center for Autophagy, Recycling and Metabolism, Danish Cancer Society Research Center, Strandboulevarden 49, 2100 Copenhagen, Denmark.
  • 2 Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada Department of Urologic Sciences, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
  • 3 Unit of Cell Death and Metabolism, Center for Autophagy, Recycling and Metabolism, Danish Cancer Society Research Center, Strandboulevarden 49, 2100 Copenhagen, Denmark mj@cancer.dk.
PMID: 26721387 DOI: 10.1093/nar/gkv1526
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.

Figures