The nuclear oncogene SET controls DNA repair by KAP1 and HP1 retention to chromatin

Alkmini Kalousi; Anne Sophie Hoffbeck; Platonas N. Selemenakis; Jordan Pinder; Kienan I. Savage; Kum Kum Khanna; Laurent Brino; Graham Dellaire; Vassilis G. Gorgoulis; Evi Soutoglou

doi:10.1016/j.celrep.2015.03.005

The nuclear oncogene SET controls DNA repair by KAP1 and HP1 retention to chromatin

Alkmini Kalousi, Anne Sophie Hoffbeck, Platonas N. Selemenakis, Jordan Pinder, Kienan I. Savage, Kum Kum Khanna, Laurent Brino, Graham Dellaire, Vassilis G. Gorgoulis, Evi Soutoglou

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83 Citas (Scopus)

Resumen

Cells experience damage from exogenous and endogenous sources that endanger genome stability. Several cellular pathways have evolved to detect DNA damage and mediate its repair. Although many proteins have been implicated in these processes, only recent studies have revealed how they operate in the context of high-ordered chromatin structure. Here, we identify the nuclear oncogene SET (I2PP2A) as a modulator of DNA damage response (DDR) and repair in chromatin surrounding double-strand breaks (DSBs). We demonstrate that depletion of SET increases DDR and survival in the presence of radiomimetic drugs, while overexpression of SET impairs DDR and homologous recombination (HR)-mediated DNA repair. SET interacts with the Kruppel-associated box (KRAB)-associated co-repressor KAP1, and its overexpression results inthe sustained retention of KAP1 and Heterochromatin protein 1 (HP1) on chromatin. Our results are consistent with a model in which SET-mediated chromatin compaction triggers an inhibition of DNA end resection and HR.

Idioma original	English
Páginas (desde-hasta)	149-163
Número de páginas	15
Publicación	Cell Reports
Volumen	11
N.º	1
DOI	https://doi.org/10.1016/j.celrep.2015.03.005
Estado	Published - abr. 7 2015

Nota bibliográfica

Funding Information:
We thank Thomais Papamarcaki (University of Ioannina) for the GFP-SET plasmid. A.K. was supported by the Fondation ARC; A.-S.H. was supported by Allocation Presidence fellowhip and Fondation pour la Recherche Médicale (FRM); and research in the E.S. laboratory is funded by the Human Frontiers Science program (HFSP CDA), the Agence Nationale de la Recherché (program Blanc), the Centre National de la Recherche Scientifique (CNRS, ATIP), the Institut National du Cancer (INCA libre) and the European FP7 framework (Marie Curie Reintegration grant), the Fondation Schlumberger (FSER), and the EMBO Young Investigator Program (EMBO YIP). V.G.G. is financially supported by the Greek GSRT program of Excellence II (Aristeia II). Work in the G.D. laboratory was supported by a Discover Grant from the Natural Science and Engineering Research Council (NSERC), and J.P. was supported by a Postdoctoral trainee award from the Beatrice Hunter Cancer Research Institute (BHCRI) with funds provided by Harvey Graham Cancer Research Fund as part of The Terry Fox Strategic Health Research Training Program in Cancer Research at CIHR. K.K.K. acknowledges the National Health and Medical Research Council (NHMRC) Senior Principal Research Fellowships (ID 613638) and NHMRC Program grant (ID 1017028).

Publisher Copyright:
© 2015 The Authors.

ASJC Scopus Subject Areas

General Biochemistry,Genetics and Molecular Biology

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10.1016/j.celrep.2015.03.005

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title = "The nuclear oncogene SET controls DNA repair by KAP1 and HP1 retention to chromatin",

abstract = "Cells experience damage from exogenous and endogenous sources that endanger genome stability. Several cellular pathways have evolved to detect DNA damage and mediate its repair. Although many proteins have been implicated in these processes, only recent studies have revealed how they operate in the context of high-ordered chromatin structure. Here, we identify the nuclear oncogene SET (I2PP2A) as a modulator of DNA damage response (DDR) and repair in chromatin surrounding double-strand breaks (DSBs). We demonstrate that depletion of SET increases DDR and survival in the presence of radiomimetic drugs, while overexpression of SET impairs DDR and homologous recombination (HR)-mediated DNA repair. SET interacts with the Kruppel-associated box (KRAB)-associated co-repressor KAP1, and its overexpression results inthe sustained retention of KAP1 and Heterochromatin protein 1 (HP1) on chromatin. Our results are consistent with a model in which SET-mediated chromatin compaction triggers an inhibition of DNA end resection and HR.",

author = "Alkmini Kalousi and Hoffbeck, {Anne Sophie} and Selemenakis, {Platonas N.} and Jordan Pinder and Savage, {Kienan I.} and Khanna, {Kum Kum} and Laurent Brino and Graham Dellaire and Gorgoulis, {Vassilis G.} and Evi Soutoglou",

note = "Funding Information: We thank Thomais Papamarcaki (University of Ioannina) for the GFP-SET plasmid. A.K. was supported by the Fondation ARC; A.-S.H. was supported by Allocation Presidence fellowhip and Fondation pour la Recherche M{\'e}dicale (FRM); and research in the E.S. laboratory is funded by the Human Frontiers Science program (HFSP CDA), the Agence Nationale de la Recherch{\'e} (program Blanc), the Centre National de la Recherche Scientifique (CNRS, ATIP), the Institut National du Cancer (INCA libre) and the European FP7 framework (Marie Curie Reintegration grant), the Fondation Schlumberger (FSER), and the EMBO Young Investigator Program (EMBO YIP). V.G.G. is financially supported by the Greek GSRT program of Excellence II (Aristeia II). Work in the G.D. laboratory was supported by a Discover Grant from the Natural Science and Engineering Research Council (NSERC), and J.P. was supported by a Postdoctoral trainee award from the Beatrice Hunter Cancer Research Institute (BHCRI) with funds provided by Harvey Graham Cancer Research Fund as part of The Terry Fox Strategic Health Research Training Program in Cancer Research at CIHR. K.K.K. acknowledges the National Health and Medical Research Council (NHMRC) Senior Principal Research Fellowships (ID 613638) and NHMRC Program grant (ID 1017028). Publisher Copyright: {\textcopyright} 2015 The Authors.",

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AU - Kalousi, Alkmini

AU - Hoffbeck, Anne Sophie

AU - Selemenakis, Platonas N.

AU - Pinder, Jordan

AU - Savage, Kienan I.

AU - Khanna, Kum Kum

AU - Brino, Laurent

AU - Dellaire, Graham

AU - Gorgoulis, Vassilis G.

AU - Soutoglou, Evi

N1 - Funding Information: We thank Thomais Papamarcaki (University of Ioannina) for the GFP-SET plasmid. A.K. was supported by the Fondation ARC; A.-S.H. was supported by Allocation Presidence fellowhip and Fondation pour la Recherche Médicale (FRM); and research in the E.S. laboratory is funded by the Human Frontiers Science program (HFSP CDA), the Agence Nationale de la Recherché (program Blanc), the Centre National de la Recherche Scientifique (CNRS, ATIP), the Institut National du Cancer (INCA libre) and the European FP7 framework (Marie Curie Reintegration grant), the Fondation Schlumberger (FSER), and the EMBO Young Investigator Program (EMBO YIP). V.G.G. is financially supported by the Greek GSRT program of Excellence II (Aristeia II). Work in the G.D. laboratory was supported by a Discover Grant from the Natural Science and Engineering Research Council (NSERC), and J.P. was supported by a Postdoctoral trainee award from the Beatrice Hunter Cancer Research Institute (BHCRI) with funds provided by Harvey Graham Cancer Research Fund as part of The Terry Fox Strategic Health Research Training Program in Cancer Research at CIHR. K.K.K. acknowledges the National Health and Medical Research Council (NHMRC) Senior Principal Research Fellowships (ID 613638) and NHMRC Program grant (ID 1017028). Publisher Copyright: © 2015 The Authors.

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N2 - Cells experience damage from exogenous and endogenous sources that endanger genome stability. Several cellular pathways have evolved to detect DNA damage and mediate its repair. Although many proteins have been implicated in these processes, only recent studies have revealed how they operate in the context of high-ordered chromatin structure. Here, we identify the nuclear oncogene SET (I2PP2A) as a modulator of DNA damage response (DDR) and repair in chromatin surrounding double-strand breaks (DSBs). We demonstrate that depletion of SET increases DDR and survival in the presence of radiomimetic drugs, while overexpression of SET impairs DDR and homologous recombination (HR)-mediated DNA repair. SET interacts with the Kruppel-associated box (KRAB)-associated co-repressor KAP1, and its overexpression results inthe sustained retention of KAP1 and Heterochromatin protein 1 (HP1) on chromatin. Our results are consistent with a model in which SET-mediated chromatin compaction triggers an inhibition of DNA end resection and HR.

AB - Cells experience damage from exogenous and endogenous sources that endanger genome stability. Several cellular pathways have evolved to detect DNA damage and mediate its repair. Although many proteins have been implicated in these processes, only recent studies have revealed how they operate in the context of high-ordered chromatin structure. Here, we identify the nuclear oncogene SET (I2PP2A) as a modulator of DNA damage response (DDR) and repair in chromatin surrounding double-strand breaks (DSBs). We demonstrate that depletion of SET increases DDR and survival in the presence of radiomimetic drugs, while overexpression of SET impairs DDR and homologous recombination (HR)-mediated DNA repair. SET interacts with the Kruppel-associated box (KRAB)-associated co-repressor KAP1, and its overexpression results inthe sustained retention of KAP1 and Heterochromatin protein 1 (HP1) on chromatin. Our results are consistent with a model in which SET-mediated chromatin compaction triggers an inhibition of DNA end resection and HR.

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The nuclear oncogene SET controls DNA repair by KAP1 and HP1 retention to chromatin

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