UV-triggered p21 degradation facilitates damaged-DNA replication and preserves genomic stability

Autores
Mansilla, Sabrina Florencia; Soria, Gastón; Vallerga, María Belén; Habif, Martin; Martínez López, Wilner; Prives, Carol; Gottifredi, Vanesa
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Although many genotoxic treatments upregulate the cyclin kinase inhibitor p21, agents such as UV irradiation trigger p21 degradation. This suggests that p21 blocks a process relevant for the cellular response to UV. Here, we show that forced p21 stabilization after UV strongly impairs damaged-DNA replication, which is associated with permanent deficiencies in the recruitment of DNA polymerases from the Y family involved in translesion DNA synthesis), with the accumulation of DNA damage markers and increased genomic instability. Remarkably, such noxious effects disappear when disrupting the proliferating cell nuclear antigen (PCNA) interacting motif of stable p21, thus suggesting that the release of PCNA from p21 interaction is sufficient to allow the recruitment to PCNA of partners (such as Y polymerases) relevant for the UV response. Expression of degradable p21 only transiently delays early replication events and Y polymerase recruitment after UV irradiation. These temporary defects disappear in a manner that correlates with p21 degradation with no detectable consequences on later replication events or genomic stability. Together, our findings suggest that the biological role of UV-triggered p21 degradation is to prevent replication defects by facilitating the tolerance of UV-induced DNA lesions.
Fil: Mansilla, Sabrina Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires(i); Argentina; Fundación Instituto Leloir; Argentina;
Fil: Soria, Gastón. Fundación Instituto Leloir. Laboratorio de Ciclo Celular y Estabilidad Genómica; Argentina;
Fil: Vallerga, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires(i); Argentina; Fundación Instituto Leloir. Laboratorio de Ciclo Celular y Estabilidad Genómica; Argentina;
Fil: Habif, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires(i); Argentina; Fundación Instituto Leloir. Laboratorio de Ciclo Celular y Estabilidad Genómica; Argentina;
Fil: Martínez López, Wilner. Fundación Instituto Leloir. Laboratorio de Ciclo Celular y Estabilidad Genómica; Argentina; Ministerio de Educación y Cultura. Instituto de Investigaciones Biológicas Clemente Estable; Uruguay;
Fil: Prives, Carol. Columbia University. Department of Biological Sciences; Estados Unidos de América;
Fil: Gottifredi, Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires(i); Argentina;
Materia
p21
Translesion DNA synthesis
Genome instability
PCNA
DNA
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/1682
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/1682
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling UV-triggered p21 degradation facilitates damaged-DNA replication and preserves genomic stabilityMansilla, Sabrina FlorenciaSoria, GastónVallerga, María BelénHabif, MartinMartínez López, WilnerPrives, CarolGottifredi, Vanesap21Translesion DNA synthesisGenome instabilityPCNADNAhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Although many genotoxic treatments upregulate the cyclin kinase inhibitor p21, agents such as UV irradiation trigger p21 degradation. This suggests that p21 blocks a process relevant for the cellular response to UV. Here, we show that forced p21 stabilization after UV strongly impairs damaged-DNA replication, which is associated with permanent deficiencies in the recruitment of DNA polymerases from the Y family involved in translesion DNA synthesis), with the accumulation of DNA damage markers and increased genomic instability. Remarkably, such noxious effects disappear when disrupting the proliferating cell nuclear antigen (PCNA) interacting motif of stable p21, thus suggesting that the release of PCNA from p21 interaction is sufficient to allow the recruitment to PCNA of partners (such as Y polymerases) relevant for the UV response. Expression of degradable p21 only transiently delays early replication events and Y polymerase recruitment after UV irradiation. These temporary defects disappear in a manner that correlates with p21 degradation with no detectable consequences on later replication events or genomic stability. Together, our findings suggest that the biological role of UV-triggered p21 degradation is to prevent replication defects by facilitating the tolerance of UV-induced DNA lesions.Fil: Mansilla, Sabrina Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires(i); Argentina; Fundación Instituto Leloir; Argentina;Fil: Soria, Gastón. Fundación Instituto Leloir. Laboratorio de Ciclo Celular y Estabilidad Genómica; Argentina;Fil: Vallerga, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires(i); Argentina; Fundación Instituto Leloir. Laboratorio de Ciclo Celular y Estabilidad Genómica; Argentina;Fil: Habif, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires(i); Argentina; Fundación Instituto Leloir. Laboratorio de Ciclo Celular y Estabilidad Genómica; Argentina;Fil: Martínez López, Wilner. Fundación Instituto Leloir. Laboratorio de Ciclo Celular y Estabilidad Genómica; Argentina; Ministerio de Educación y Cultura. Instituto de Investigaciones Biológicas Clemente Estable; Uruguay;Fil: Prives, Carol. Columbia University. Department of Biological Sciences; Estados Unidos de América;Fil: Gottifredi, Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires(i); Argentina;Oxford University Press2013-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/1682Mansilla, Sabrina Florencia; Soria, Gastón; Vallerga, María Belén; Habif, Martin; Martínez López, Wilner; et al.; UV-triggered p21 degradation facilitates damaged-DNA replication and preserves genomic stability; Oxford University Press; Nucleic Acids Research; 41; 14; 5-2013; 6942–69510305-10481362-4962enginfo:eu-repo/semantics/altIdentifier/doi/doi:10.1093/nar/gkt475info:eu-repo/semantics/altIdentifier/url/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3737556/info:eu-repo/semantics/altIdentifier/url/http://nar.oxfordjournals.org/content/41/14/6942.full-text-lowres.pdfinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:48:36Zoai:ri.conicet.gov.ar:11336/1682instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:48:37.097CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv UV-triggered p21 degradation facilitates damaged-DNA replication and preserves genomic stability
title UV-triggered p21 degradation facilitates damaged-DNA replication and preserves genomic stability
spellingShingle UV-triggered p21 degradation facilitates damaged-DNA replication and preserves genomic stability
Mansilla, Sabrina Florencia
p21
Translesion DNA synthesis
Genome instability
PCNA
DNA
title_short UV-triggered p21 degradation facilitates damaged-DNA replication and preserves genomic stability
title_full UV-triggered p21 degradation facilitates damaged-DNA replication and preserves genomic stability
title_fullStr UV-triggered p21 degradation facilitates damaged-DNA replication and preserves genomic stability
title_full_unstemmed UV-triggered p21 degradation facilitates damaged-DNA replication and preserves genomic stability
title_sort UV-triggered p21 degradation facilitates damaged-DNA replication and preserves genomic stability
dc.creator.none.fl_str_mv Mansilla, Sabrina Florencia
Soria, Gastón
Vallerga, María Belén
Habif, Martin
Martínez López, Wilner
Prives, Carol
Gottifredi, Vanesa
author Mansilla, Sabrina Florencia
author_facet Mansilla, Sabrina Florencia
Soria, Gastón
Vallerga, María Belén
Habif, Martin
Martínez López, Wilner
Prives, Carol
Gottifredi, Vanesa
author_role author
author2 Soria, Gastón
Vallerga, María Belén
Habif, Martin
Martínez López, Wilner
Prives, Carol
Gottifredi, Vanesa
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv p21
Translesion DNA synthesis
Genome instability
PCNA
DNA
topic p21
Translesion DNA synthesis
Genome instability
PCNA
DNA
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Although many genotoxic treatments upregulate the cyclin kinase inhibitor p21, agents such as UV irradiation trigger p21 degradation. This suggests that p21 blocks a process relevant for the cellular response to UV. Here, we show that forced p21 stabilization after UV strongly impairs damaged-DNA replication, which is associated with permanent deficiencies in the recruitment of DNA polymerases from the Y family involved in translesion DNA synthesis), with the accumulation of DNA damage markers and increased genomic instability. Remarkably, such noxious effects disappear when disrupting the proliferating cell nuclear antigen (PCNA) interacting motif of stable p21, thus suggesting that the release of PCNA from p21 interaction is sufficient to allow the recruitment to PCNA of partners (such as Y polymerases) relevant for the UV response. Expression of degradable p21 only transiently delays early replication events and Y polymerase recruitment after UV irradiation. These temporary defects disappear in a manner that correlates with p21 degradation with no detectable consequences on later replication events or genomic stability. Together, our findings suggest that the biological role of UV-triggered p21 degradation is to prevent replication defects by facilitating the tolerance of UV-induced DNA lesions.
Fil: Mansilla, Sabrina Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires(i); Argentina; Fundación Instituto Leloir; Argentina;
Fil: Soria, Gastón. Fundación Instituto Leloir. Laboratorio de Ciclo Celular y Estabilidad Genómica; Argentina;
Fil: Vallerga, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires(i); Argentina; Fundación Instituto Leloir. Laboratorio de Ciclo Celular y Estabilidad Genómica; Argentina;
Fil: Habif, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires(i); Argentina; Fundación Instituto Leloir. Laboratorio de Ciclo Celular y Estabilidad Genómica; Argentina;
Fil: Martínez López, Wilner. Fundación Instituto Leloir. Laboratorio de Ciclo Celular y Estabilidad Genómica; Argentina; Ministerio de Educación y Cultura. Instituto de Investigaciones Biológicas Clemente Estable; Uruguay;
Fil: Prives, Carol. Columbia University. Department of Biological Sciences; Estados Unidos de América;
Fil: Gottifredi, Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires(i); Argentina;
description Although many genotoxic treatments upregulate the cyclin kinase inhibitor p21, agents such as UV irradiation trigger p21 degradation. This suggests that p21 blocks a process relevant for the cellular response to UV. Here, we show that forced p21 stabilization after UV strongly impairs damaged-DNA replication, which is associated with permanent deficiencies in the recruitment of DNA polymerases from the Y family involved in translesion DNA synthesis), with the accumulation of DNA damage markers and increased genomic instability. Remarkably, such noxious effects disappear when disrupting the proliferating cell nuclear antigen (PCNA) interacting motif of stable p21, thus suggesting that the release of PCNA from p21 interaction is sufficient to allow the recruitment to PCNA of partners (such as Y polymerases) relevant for the UV response. Expression of degradable p21 only transiently delays early replication events and Y polymerase recruitment after UV irradiation. These temporary defects disappear in a manner that correlates with p21 degradation with no detectable consequences on later replication events or genomic stability. Together, our findings suggest that the biological role of UV-triggered p21 degradation is to prevent replication defects by facilitating the tolerance of UV-induced DNA lesions.
publishDate 2013
dc.date.none.fl_str_mv 2013-05
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/1682
Mansilla, Sabrina Florencia; Soria, Gastón; Vallerga, María Belén; Habif, Martin; Martínez López, Wilner; et al.; UV-triggered p21 degradation facilitates damaged-DNA replication and preserves genomic stability; Oxford University Press; Nucleic Acids Research; 41; 14; 5-2013; 6942–6951
0305-1048
1362-4962
url http://hdl.handle.net/11336/1682
identifier_str_mv Mansilla, Sabrina Florencia; Soria, Gastón; Vallerga, María Belén; Habif, Martin; Martínez López, Wilner; et al.; UV-triggered p21 degradation facilitates damaged-DNA replication and preserves genomic stability; Oxford University Press; Nucleic Acids Research; 41; 14; 5-2013; 6942–6951
0305-1048
1362-4962
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/doi:10.1093/nar/gkt475
info:eu-repo/semantics/altIdentifier/url/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3737556/
info:eu-repo/semantics/altIdentifier/url/http://nar.oxfordjournals.org/content/41/14/6942.full-text-lowres.pdf
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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