Impact of the interplay between stemness features, p53 and pol iota on replication pathway choices

Autores
Ihle, Michaela; Biber, Stephanie; Schroeder, Insa S; Blattner, Christine; Deniz, Miriam; Damia, Giovanna; Gottifredi, Vanesa; Wiesmuller, Lisa
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Using human embryonic, adult and cancer stem cells/stem cell-like cells (SCs), we demonstrate that DNA replication speed differs in SCs and their differentiated counterparts. While SCs decelerate DNA replication, differentiated cells synthesize DNA faster and accumulate DNA damage. Notably, both replication phenotypes depend on p53 and polymerase iota (POLι). By exploring protein interactions and newly synthesized DNA, we show that SCs promote complex formation of p53 and POLι at replication sites. Intriguingly, in SCs the translocase ZRANB3 is recruited to POLι and required for slow-down of DNA replication. The known role of ZRANB3 in fork reversal suggests that the p53-POLι complex mediates slow but safe bypass of replication barriers in SCs. In differentiated cells, POLι localizes more transiently to sites of DNA synthesis and no longer interacts with p53 facilitating fast POLι-dependent DNA replication. In this alternative scenario, POLι associates with the p53 target p21, which antagonizes PCNA poly-ubiquitination and, thereby potentially disfavors the recruitment of translocases. Altogether, we provide evidence for diametrically opposed DNA replication phenotypes in SCs and their differentiated counterparts putting DNA replication-based strategies in the spotlight for the creation of therapeutic opportunities targeting SCs.
Fil: Ihle, Michaela. Universitat Ulm; Alemania
Fil: Biber, Stephanie. Universitat Ulm; Alemania
Fil: Schroeder, Insa S. GSI Helmholtz Center for Heavy Ion Research; Alemania
Fil: Blattner, Christine. Karlsruhe Institute of Technology; Alemania
Fil: Deniz, Miriam. Universitat Ulm; Alemania
Fil: Damia, Giovanna. Istituto di Ricerche Farmacologiche Mario Negri; Italia
Fil: Gottifredi, Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Wiesmuller, Lisa. Universitat Ulm; Alemania
Materia
P53
Pol iota
DNA replication
Stemness
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/167150
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/167150
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Impact of the interplay between stemness features, p53 and pol iota on replication pathway choicesIhle, MichaelaBiber, StephanieSchroeder, Insa SBlattner, ChristineDeniz, MiriamDamia, GiovannaGottifredi, VanesaWiesmuller, LisaP53Pol iotaDNA replicationStemnesshttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Using human embryonic, adult and cancer stem cells/stem cell-like cells (SCs), we demonstrate that DNA replication speed differs in SCs and their differentiated counterparts. While SCs decelerate DNA replication, differentiated cells synthesize DNA faster and accumulate DNA damage. Notably, both replication phenotypes depend on p53 and polymerase iota (POLι). By exploring protein interactions and newly synthesized DNA, we show that SCs promote complex formation of p53 and POLι at replication sites. Intriguingly, in SCs the translocase ZRANB3 is recruited to POLι and required for slow-down of DNA replication. The known role of ZRANB3 in fork reversal suggests that the p53-POLι complex mediates slow but safe bypass of replication barriers in SCs. In differentiated cells, POLι localizes more transiently to sites of DNA synthesis and no longer interacts with p53 facilitating fast POLι-dependent DNA replication. In this alternative scenario, POLι associates with the p53 target p21, which antagonizes PCNA poly-ubiquitination and, thereby potentially disfavors the recruitment of translocases. Altogether, we provide evidence for diametrically opposed DNA replication phenotypes in SCs and their differentiated counterparts putting DNA replication-based strategies in the spotlight for the creation of therapeutic opportunities targeting SCs.Fil: Ihle, Michaela. Universitat Ulm; AlemaniaFil: Biber, Stephanie. Universitat Ulm; AlemaniaFil: Schroeder, Insa S. GSI Helmholtz Center for Heavy Ion Research; AlemaniaFil: Blattner, Christine. Karlsruhe Institute of Technology; AlemaniaFil: Deniz, Miriam. Universitat Ulm; AlemaniaFil: Damia, Giovanna. Istituto di Ricerche Farmacologiche Mario Negri; ItaliaFil: Gottifredi, Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Wiesmuller, Lisa. Universitat Ulm; AlemaniaOxford University Press2021-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/167150Ihle, Michaela; Biber, Stephanie; Schroeder, Insa S; Blattner, Christine; Deniz, Miriam; et al.; Impact of the interplay between stemness features, p53 and pol iota on replication pathway choices; Oxford University Press; Nucleic Acids Research; 49; 13; 7-2021; 7457-74750305-10481362-4962CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/nar/article/49/13/7457/6308984info:eu-repo/semantics/altIdentifier/doi/10.1093/nar/gkab526info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:38:08Zoai:ri.conicet.gov.ar:11336/167150instacron: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 09:38:09.072CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Impact of the interplay between stemness features, p53 and pol iota on replication pathway choices
title Impact of the interplay between stemness features, p53 and pol iota on replication pathway choices
spellingShingle Impact of the interplay between stemness features, p53 and pol iota on replication pathway choices
Ihle, Michaela
P53
Pol iota
DNA replication
Stemness
title_short Impact of the interplay between stemness features, p53 and pol iota on replication pathway choices
title_full Impact of the interplay between stemness features, p53 and pol iota on replication pathway choices
title_fullStr Impact of the interplay between stemness features, p53 and pol iota on replication pathway choices
title_full_unstemmed Impact of the interplay between stemness features, p53 and pol iota on replication pathway choices
title_sort Impact of the interplay between stemness features, p53 and pol iota on replication pathway choices
dc.creator.none.fl_str_mv Ihle, Michaela
Biber, Stephanie
Schroeder, Insa S
Blattner, Christine
Deniz, Miriam
Damia, Giovanna
Gottifredi, Vanesa
Wiesmuller, Lisa
author Ihle, Michaela
author_facet Ihle, Michaela
Biber, Stephanie
Schroeder, Insa S
Blattner, Christine
Deniz, Miriam
Damia, Giovanna
Gottifredi, Vanesa
Wiesmuller, Lisa
author_role author
author2 Biber, Stephanie
Schroeder, Insa S
Blattner, Christine
Deniz, Miriam
Damia, Giovanna
Gottifredi, Vanesa
Wiesmuller, Lisa
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv P53
Pol iota
DNA replication
Stemness
topic P53
Pol iota
DNA replication
Stemness
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Using human embryonic, adult and cancer stem cells/stem cell-like cells (SCs), we demonstrate that DNA replication speed differs in SCs and their differentiated counterparts. While SCs decelerate DNA replication, differentiated cells synthesize DNA faster and accumulate DNA damage. Notably, both replication phenotypes depend on p53 and polymerase iota (POLι). By exploring protein interactions and newly synthesized DNA, we show that SCs promote complex formation of p53 and POLι at replication sites. Intriguingly, in SCs the translocase ZRANB3 is recruited to POLι and required for slow-down of DNA replication. The known role of ZRANB3 in fork reversal suggests that the p53-POLι complex mediates slow but safe bypass of replication barriers in SCs. In differentiated cells, POLι localizes more transiently to sites of DNA synthesis and no longer interacts with p53 facilitating fast POLι-dependent DNA replication. In this alternative scenario, POLι associates with the p53 target p21, which antagonizes PCNA poly-ubiquitination and, thereby potentially disfavors the recruitment of translocases. Altogether, we provide evidence for diametrically opposed DNA replication phenotypes in SCs and their differentiated counterparts putting DNA replication-based strategies in the spotlight for the creation of therapeutic opportunities targeting SCs.
Fil: Ihle, Michaela. Universitat Ulm; Alemania
Fil: Biber, Stephanie. Universitat Ulm; Alemania
Fil: Schroeder, Insa S. GSI Helmholtz Center for Heavy Ion Research; Alemania
Fil: Blattner, Christine. Karlsruhe Institute of Technology; Alemania
Fil: Deniz, Miriam. Universitat Ulm; Alemania
Fil: Damia, Giovanna. Istituto di Ricerche Farmacologiche Mario Negri; Italia
Fil: Gottifredi, Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Wiesmuller, Lisa. Universitat Ulm; Alemania
description Using human embryonic, adult and cancer stem cells/stem cell-like cells (SCs), we demonstrate that DNA replication speed differs in SCs and their differentiated counterparts. While SCs decelerate DNA replication, differentiated cells synthesize DNA faster and accumulate DNA damage. Notably, both replication phenotypes depend on p53 and polymerase iota (POLι). By exploring protein interactions and newly synthesized DNA, we show that SCs promote complex formation of p53 and POLι at replication sites. Intriguingly, in SCs the translocase ZRANB3 is recruited to POLι and required for slow-down of DNA replication. The known role of ZRANB3 in fork reversal suggests that the p53-POLι complex mediates slow but safe bypass of replication barriers in SCs. In differentiated cells, POLι localizes more transiently to sites of DNA synthesis and no longer interacts with p53 facilitating fast POLι-dependent DNA replication. In this alternative scenario, POLι associates with the p53 target p21, which antagonizes PCNA poly-ubiquitination and, thereby potentially disfavors the recruitment of translocases. Altogether, we provide evidence for diametrically opposed DNA replication phenotypes in SCs and their differentiated counterparts putting DNA replication-based strategies in the spotlight for the creation of therapeutic opportunities targeting SCs.
publishDate 2021
dc.date.none.fl_str_mv 2021-07
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/11336/167150
Ihle, Michaela; Biber, Stephanie; Schroeder, Insa S; Blattner, Christine; Deniz, Miriam; et al.; Impact of the interplay between stemness features, p53 and pol iota on replication pathway choices; Oxford University Press; Nucleic Acids Research; 49; 13; 7-2021; 7457-7475
0305-1048
1362-4962
CONICET Digital
CONICET
url http://hdl.handle.net/11336/167150
identifier_str_mv Ihle, Michaela; Biber, Stephanie; Schroeder, Insa S; Blattner, Christine; Deniz, Miriam; et al.; Impact of the interplay between stemness features, p53 and pol iota on replication pathway choices; Oxford University Press; Nucleic Acids Research; 49; 13; 7-2021; 7457-7475
0305-1048
1362-4962
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/nar/article/49/13/7457/6308984
info:eu-repo/semantics/altIdentifier/doi/10.1093/nar/gkab526
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc/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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