VRK1 phosphorylates Tip60/KAT5 and is required for H4K16 acetylation in response to DNA damage

Dynamic remodeling of chromatin requires acetylation and methylation of histones, frequently affecting the same lysine residue. These alternative epigenetic modifications require the coordination of enzymes, writers and erasers, mediating them such as acetylases and deacetylases. In cells in G0/G1,...

Descripción completa

Detalles Bibliográficos
Autores: García González, Raúl, Morejón-García, Patricia, Campillo-Marcos, Ignacio, Salzano, Marcella
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/226570
Acceso en línea:http://hdl.handle.net/10261/226570
Access Level:acceso abierto
Palabra clave:Phosphorylation
Histone H4
Acetylation
DNA-damage response
Nucleosomal histone kinase-1
id ES_faeeb9ba986c1ff1bb27682bdb220f34
oai_identifier_str oai:digital.csic.es:10261/226570
network_acronym_str ES
network_name_str España
repository_id_str
spelling VRK1 phosphorylates Tip60/KAT5 and is required for H4K16 acetylation in response to DNA damageGarcía González, RaúlMorejón-García, PatriciaCampillo-Marcos, IgnacioSalzano, MarcellaPhosphorylationHistone H4AcetylationDNA-damage responseNucleosomal histone kinase-1Dynamic remodeling of chromatin requires acetylation and methylation of histones, frequently affecting the same lysine residue. These alternative epigenetic modifications require the coordination of enzymes, writers and erasers, mediating them such as acetylases and deacetylases. In cells in G0/G1, DNA damage induced by doxorubicin causes an increase in histone H4K16ac, a marker of chromatin relaxation. In this context, we studied the role that VRK1, a chromatin kinase activated by DNA damage, plays in this early step. VRK1 depletion or MG149, a Tip60/KAT5 inhibitor, cause a loss of H4K16ac. DNA damage induces the phosphorylation of Tip60 mediated by VRK1 in the chromatin fraction. VRK1 directly interacts with and phosphorylates Tip60. Furthermore, the phosphorylation of Tip60 induced by doxorubicin is lost by depletion of VRK1 in both ATM +/+ and ATM−/− cells. Kinase-active VRK1, but not kinase-dead VRK1, rescues Tip60 phosphorylation induced by DNA damage independently of ATM. The Tip60 phosphorylation by VRK1 is necessary for the activating acetylation of ATM, and subsequent ATM autophosphorylation, and both are lost by VRK1 depletion. These results support that the VRK1 chromatin kinase is an upstream regulator of the initial acetylation of histones, and an early step in DNA damage responses (DDR).This work was supported by grants from Agencia Estatal de Investigación-Ministerio de Economía y Competitividad-FEDER [SAF2016-75744-R; RED2018-102801-T, PID2019-105610RB-I00] Consejería de Educación de la Junta de Castilla y León-ERDF [CLC-2017-01, and UIC-258] to P.A.L., R.G.-G, P.M.-G. and I.C.-M. were supported by Consejería de Educación-Junta de Castilla y León-Fondo Social Europeo (ESF), Ministerio de Educación y Universidades [FPU 16-01883] and MINECO-FPI [BES-2014-067729] predoctoral fellowships respectively.Multidisciplinary Digital Publishing InstituteMinisterio de Economía y Competitividad (España)European CommissionMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Junta de Castilla y LeónConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2021202120202021info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/226570reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016-75744-Rinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RED2018-102801-TRED2018-102801-T/AEI/10.13039/501100011033info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-105610RB-I00PID2019-105610RB-I00/AEI/10.13039/501100011033http://dx.doi.org/10.3390/cancers12102986Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2265702026-05-22T06:33:51Z
dc.title.none.fl_str_mv VRK1 phosphorylates Tip60/KAT5 and is required for H4K16 acetylation in response to DNA damage
title VRK1 phosphorylates Tip60/KAT5 and is required for H4K16 acetylation in response to DNA damage
spellingShingle VRK1 phosphorylates Tip60/KAT5 and is required for H4K16 acetylation in response to DNA damage
García González, Raúl
Phosphorylation
Histone H4
Acetylation
DNA-damage response
Nucleosomal histone kinase-1
title_short VRK1 phosphorylates Tip60/KAT5 and is required for H4K16 acetylation in response to DNA damage
title_full VRK1 phosphorylates Tip60/KAT5 and is required for H4K16 acetylation in response to DNA damage
title_fullStr VRK1 phosphorylates Tip60/KAT5 and is required for H4K16 acetylation in response to DNA damage
title_full_unstemmed VRK1 phosphorylates Tip60/KAT5 and is required for H4K16 acetylation in response to DNA damage
title_sort VRK1 phosphorylates Tip60/KAT5 and is required for H4K16 acetylation in response to DNA damage
dc.creator.none.fl_str_mv García González, Raúl
Morejón-García, Patricia
Campillo-Marcos, Ignacio
Salzano, Marcella
author García González, Raúl
author_facet García González, Raúl
Morejón-García, Patricia
Campillo-Marcos, Ignacio
Salzano, Marcella
author_role author
author2 Morejón-García, Patricia
Campillo-Marcos, Ignacio
Salzano, Marcella
author2_role author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
European Commission
Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
Junta de Castilla y León
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Phosphorylation
Histone H4
Acetylation
DNA-damage response
Nucleosomal histone kinase-1
topic Phosphorylation
Histone H4
Acetylation
DNA-damage response
Nucleosomal histone kinase-1
description Dynamic remodeling of chromatin requires acetylation and methylation of histones, frequently affecting the same lysine residue. These alternative epigenetic modifications require the coordination of enzymes, writers and erasers, mediating them such as acetylases and deacetylases. In cells in G0/G1, DNA damage induced by doxorubicin causes an increase in histone H4K16ac, a marker of chromatin relaxation. In this context, we studied the role that VRK1, a chromatin kinase activated by DNA damage, plays in this early step. VRK1 depletion or MG149, a Tip60/KAT5 inhibitor, cause a loss of H4K16ac. DNA damage induces the phosphorylation of Tip60 mediated by VRK1 in the chromatin fraction. VRK1 directly interacts with and phosphorylates Tip60. Furthermore, the phosphorylation of Tip60 induced by doxorubicin is lost by depletion of VRK1 in both ATM +/+ and ATM−/− cells. Kinase-active VRK1, but not kinase-dead VRK1, rescues Tip60 phosphorylation induced by DNA damage independently of ATM. The Tip60 phosphorylation by VRK1 is necessary for the activating acetylation of ATM, and subsequent ATM autophosphorylation, and both are lost by VRK1 depletion. These results support that the VRK1 chromatin kinase is an upstream regulator of the initial acetylation of histones, and an early step in DNA damage responses (DDR).
publishDate 2020
dc.date.none.fl_str_mv 2020
2021
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/226570
url http://hdl.handle.net/10261/226570
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016-75744-R
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RED2018-102801-T
RED2018-102801-T/AEI/10.13039/501100011033
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-105610RB-I00
PID2019-105610RB-I00/AEI/10.13039/501100011033
http://dx.doi.org/10.3390/cancers12102986
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869425283563520000
score 15,812429

Similares en LA Referencia