TY - JOUR

T1 - SPOC1 modulates DNA repair by regulating key determinants of chromatin compaction and DNA damage response

AU - Mund, Andreas

AU - Schubert, Tobias

AU - Staege, Hannah

AU - Kinkley, Sarah

AU - Reumann, Kerstin

AU - Kriegs, Malte

AU - Fritsch, Lauriane

AU - Battisti, Valentine

AU - Ait-Si-Ali, Slimane

AU - Hoffbeck, Anne-Sophie

AU - Soutoglou, Evi

AU - Will, Hans

PY - 2012/12

Y1 - 2012/12

N2 - 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.

AB - 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.

KW - Cell Line

KW - Chromatin/metabolism

KW - DNA Breaks, Double-Stranded

KW - DNA End-Joining Repair

KW - DNA Repair

KW - DNA-Binding Proteins/metabolism

KW - Gamma Rays

KW - Heterochromatin

KW - Histone-Lysine N-Methyltransferase/metabolism

KW - Humans

KW - Radiation Tolerance

KW - Recombinational DNA Repair

KW - Repressor Proteins/metabolism

KW - Transcription Factors/metabolism

KW - Tripartite Motif-Containing Protein 28

U2 - 10.1093/nar/gks868

DO - 10.1093/nar/gks868

M3 - Journal article

C2 - 23034801

VL - 40

SP - 11363

EP - 11379

JO - Nucleic Acids Research

JF - Nucleic Acids Research

SN - 0305-1048

IS - 22

ER -