title: Hepatoma-derived growth factor-related protein 2 promotes DNA repair by homologous recombination.
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.
authors.affiliation: Unit of Cell Death and Metabolism, Center for Autophagy, Recycling and Metabolism, Danish Cancer Society Research Center, Strandboulevarden 49, 2100 Copenhagen, Denmark.
authors.forename: Annika
authors.initials: A
authors.lastname: Baude
authors.affiliation: Unit of Cell Death and Metabolism, Center for Autophagy, Recycling and Metabolism, Danish Cancer Society Research Center, Strandboulevarden 49, 2100 Copenhagen, Denmark.
authors.forename: Tania Løve
authors.initials: TL
authors.lastname: Aaes
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada Department of Urologic Sciences, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
authors.forename: Beibei
authors.initials: B
authors.lastname: Zhai
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada Department of Urologic Sciences, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
authors.forename: Nader
authors.initials: N
authors.lastname: Al-Nakouzi
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada Department of Urologic Sciences, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
authors.forename: Htoo Zarni
authors.initials: HZ
authors.lastname: Oo
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada Department of Urologic Sciences, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
authors.forename: Mads
authors.initials: M
authors.lastname: Daugaard
authors.affiliation: Unit of Cell Death and Metabolism, Center for Autophagy, Recycling and Metabolism, Danish Cancer Society Research Center, Strandboulevarden 49, 2100 Copenhagen, Denmark.
authors.forename: Mikkel
authors.initials: M
authors.lastname: Rohde
authors.affiliation: 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.
authors.forename: Marja
authors.initials: M
authors.lastname: Jäättelä
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004706:Endodeoxyribonucleases; D006367:HeLa Cells; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D059767:Recombinational DNA Repair; D051716:Replication Protein A / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D019895:Transposases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins; D018797:Cell Cycle Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D002843:Chromatin; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone; D004706:Endodeoxyribonucleases; D006657:Histones; D036341:Intercellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D051716:Replication Protein A; D014157:Transcription Factors; D019895:Transposases; C000715593:CBX1 protein, human; C541037:POGZ protein, human; D004268:DNA-Binding Proteins; D018797:Cell Cycle Proteins; C504649:PSIP1 protein, human; C051610:hepatoma-derived growth factor; C516794:RPA2 protein, human; C410741:RBBP8 protein, human