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
SN - 0305-1048
VL - 40
SP - 11363
EP - 11379
JO - Nucleic Acids Research
JF - Nucleic Acids Research
IS - 22
ER -
