title: SPOC1 modulates DNA repair by regulating key determinants of chromatin compaction and DNA damage response.
abstract: Survival time-associated plant homeodomain (PHD) finger protein in Ovarian Cancer 1 (SPOC1, also known as PHF13) is known to modulate chromatin structure and is essential for testicular stem-cell differentiation. Here we show that SPOC1 is recruited to DNA double-strand breaks (DSBs) in an ATM-dependent manner. Moreover, SPOC1 localizes at endogenous repair foci, including OPT domains and accumulates at large DSB repair foci characteristic for delayed repair at heterochromatic sites. SPOC1 depletion enhances the kinetics of ionizing radiation-induced foci (IRIF) formation after γ-irradiation (γ-IR), non-homologous end-joining (NHEJ) repair activity, and cellular radioresistance, but impairs homologous recombination (HR) repair. Conversely, SPOC1 overexpression delays IRIF formation and γH2AX expansion, reduces NHEJ repair activity and enhances cellular radiosensitivity. SPOC1 mediates dose-dependent changes in chromatin association of DNA compaction factors KAP-1, HP1-α and H3K9 methyltransferases (KMT) GLP, G9A and SETDB1. In addition, SPOC1 interacts with KAP-1 and H3K9 KMTs, inhibits KAP-1 phosphorylation and enhances H3K9 trimethylation. These findings provide the first evidence for a function of SPOC1 in DNA damage response (DDR) and repair. SPOC1 acts as a modulator of repair kinetics and choice of pathways. This involves its dose-dependent effects on DNA damage sensors, repair mediators and key regulators of chromatin structure.
authors.affiliation: Heinrich-Pette-Institute, Leibniz-Institute for Experimental Virology, Department of General Virology, Martinistrasse 52, 20251 Hamburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Mund
authors.forename: Tobias
authors.initials: T
authors.lastname: Schubert
authors.forename: Hannah
authors.initials: H
authors.lastname: Staege
authors.forename: Sarah
authors.initials: S
authors.lastname: Kinkley
authors.forename: Kerstin
authors.initials: K
authors.lastname: Reumann
authors.forename: Malte
authors.initials: M
authors.lastname: Kriegs
authors.forename: Lauriane
authors.initials: L
authors.lastname: Fritsch
authors.forename: Valentine
authors.initials: V
authors.lastname: Battisti
authors.forename: Slimane
authors.initials: S
authors.lastname: Ait-Si-Ali
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Hoffbeck
authors.forename: Evi
authors.initials: E
authors.lastname: Soutoglou
authors.forename: Hans
authors.initials: H
authors.lastname: Will
mesh_terms: D002460:Cell Line; D002843:Chromatin / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005720:Gamma Rays; D006570:Heterochromatin; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006801:Humans; D011836:Radiation Tolerance; D059767:Recombinational DNA Repair; D012097:Repressor Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D000076183:Tripartite Motif-Containing Protein 28
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D006570:Heterochromatin; C503048:PHF13 protein, human; D012097:Repressor Proteins; D014157:Transcription Factors; D011495:Histone-Lysine N-Methyltransferase; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28