Cargando…
SPOC1 modulates DNA repair by regulating key determinants of chromatin compaction and DNA damage response
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-depen...
Autores principales: | , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2012
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526275/ https://www.ncbi.nlm.nih.gov/pubmed/23034801 http://dx.doi.org/10.1093/nar/gks868 |
_version_ | 1782253533706321920 |
---|---|
author | Mund, Andreas Schubert, Tobias Staege, Hannah Kinkley, Sarah Reumann, Kerstin Kriegs, Malte Fritsch, Lauriane Battisti, Valentine Ait-Si-Ali, Slimane Hoffbeck, Anne-Sophie Soutoglou, Evi Will, Hans |
author_facet | Mund, Andreas Schubert, Tobias Staege, Hannah Kinkley, Sarah Reumann, Kerstin Kriegs, Malte Fritsch, Lauriane Battisti, Valentine Ait-Si-Ali, Slimane Hoffbeck, Anne-Sophie Soutoglou, Evi Will, Hans |
author_sort | Mund, Andreas |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3526275 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-35262752013-01-04 SPOC1 modulates DNA repair by regulating key determinants of chromatin compaction and DNA damage response Mund, Andreas Schubert, Tobias Staege, Hannah Kinkley, Sarah Reumann, Kerstin Kriegs, Malte Fritsch, Lauriane Battisti, Valentine Ait-Si-Ali, Slimane Hoffbeck, Anne-Sophie Soutoglou, Evi Will, Hans Nucleic Acids Res Genome Integrity, Repair and Replication 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. Oxford University Press 2012-12 2012-10-02 /pmc/articles/PMC3526275/ /pubmed/23034801 http://dx.doi.org/10.1093/nar/gks868 Text en © The Author(s) 2012. Published by Oxford University Press. http://creativecommons.org/licenses/by/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Genome Integrity, Repair and Replication Mund, Andreas Schubert, Tobias Staege, Hannah Kinkley, Sarah Reumann, Kerstin Kriegs, Malte Fritsch, Lauriane Battisti, Valentine Ait-Si-Ali, Slimane Hoffbeck, Anne-Sophie Soutoglou, Evi Will, Hans SPOC1 modulates DNA repair by regulating key determinants of chromatin compaction and DNA damage response |
title | SPOC1 modulates DNA repair by regulating key determinants of chromatin compaction and DNA damage response |
title_full | SPOC1 modulates DNA repair by regulating key determinants of chromatin compaction and DNA damage response |
title_fullStr | SPOC1 modulates DNA repair by regulating key determinants of chromatin compaction and DNA damage response |
title_full_unstemmed | SPOC1 modulates DNA repair by regulating key determinants of chromatin compaction and DNA damage response |
title_short | SPOC1 modulates DNA repair by regulating key determinants of chromatin compaction and DNA damage response |
title_sort | spoc1 modulates dna repair by regulating key determinants of chromatin compaction and dna damage response |
topic | Genome Integrity, Repair and Replication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526275/ https://www.ncbi.nlm.nih.gov/pubmed/23034801 http://dx.doi.org/10.1093/nar/gks868 |
work_keys_str_mv | AT mundandreas spoc1modulatesdnarepairbyregulatingkeydeterminantsofchromatincompactionanddnadamageresponse AT schuberttobias spoc1modulatesdnarepairbyregulatingkeydeterminantsofchromatincompactionanddnadamageresponse AT staegehannah spoc1modulatesdnarepairbyregulatingkeydeterminantsofchromatincompactionanddnadamageresponse AT kinkleysarah spoc1modulatesdnarepairbyregulatingkeydeterminantsofchromatincompactionanddnadamageresponse AT reumannkerstin spoc1modulatesdnarepairbyregulatingkeydeterminantsofchromatincompactionanddnadamageresponse AT kriegsmalte spoc1modulatesdnarepairbyregulatingkeydeterminantsofchromatincompactionanddnadamageresponse AT fritschlauriane spoc1modulatesdnarepairbyregulatingkeydeterminantsofchromatincompactionanddnadamageresponse AT battistivalentine spoc1modulatesdnarepairbyregulatingkeydeterminantsofchromatincompactionanddnadamageresponse AT aitsialislimane spoc1modulatesdnarepairbyregulatingkeydeterminantsofchromatincompactionanddnadamageresponse AT hoffbeckannesophie spoc1modulatesdnarepairbyregulatingkeydeterminantsofchromatincompactionanddnadamageresponse AT soutoglouevi spoc1modulatesdnarepairbyregulatingkeydeterminantsofchromatincompactionanddnadamageresponse AT willhans spoc1modulatesdnarepairbyregulatingkeydeterminantsofchromatincompactionanddnadamageresponse |