PDS5 proteins are required for proper cohesin dynamics and participate in replication fork protection.

Cohesin is a chromatin-bound complex that mediates sister chromatid cohesion and facilitates long-range interactions through DNA looping. How the transcription and replication machineries deal with the presence of cohesin on chromatin remains unclear. The dynamic association of cohesin with chromati...

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Autores: Morales, Carmen, Ruiz-Torres, Miguel, Rodríguez-Acebes, Sara, Rodríguez-Corsino, Miriam, Cisneros, David A, Peters, Jan-Michael, Lafarga, Vanesa, Megias Vazquez, Diego, Mendez, Juan, Losada, Ana
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/13272
Acceso en línea:http://hdl.handle.net/20.500.12105/13272
Access Level:acceso abierto
Palabra clave:DNA Replication
ATPases Associated with Diverse Cellular Activities
Animals
BRCA2 Protein
Cell Cycle Proteins
Cells, Cultured
Chromatin
Chromosomal Proteins, Non-Histone
DNA-Binding Proteins
HeLa Cells
Humans
MRE11 Homologue Protein
Mice
Nuclear Proteins
Rad51 Recombinase
Transcription Factors
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oai_identifier_str oai:repisalud.isciii.es:20.500.12105/13272
network_acronym_str ES
network_name_str España
repository_id_str
spelling PDS5 proteins are required for proper cohesin dynamics and participate in replication fork protection.Morales, CarmenRuiz-Torres, MiguelRodríguez-Acebes, SaraRodríguez-Corsino, MiriamCisneros, David APeters, Jan-MichaelLafarga, VanesaMegias Vazquez, DiegoMendez, JuanLosada, AnaDNA ReplicationATPases Associated with Diverse Cellular ActivitiesAnimalsBRCA2 ProteinCell Cycle ProteinsCells, CulturedChromatinChromosomal Proteins, Non-HistoneDNA-Binding ProteinsHeLa CellsHumansMRE11 Homologue ProteinMiceNuclear ProteinsRad51 RecombinaseTranscription FactorsCohesin is a chromatin-bound complex that mediates sister chromatid cohesion and facilitates long-range interactions through DNA looping. How the transcription and replication machineries deal with the presence of cohesin on chromatin remains unclear. The dynamic association of cohesin with chromatin depends on WAPL cohesin release factor (WAPL) and on PDS5 cohesin-associated factor (PDS5), which exists in two versions in vertebrate cells, PDS5A and PDS5B. Using genetic deletion in mouse embryo fibroblasts and a combination of CRISPR-mediated gene editing and RNAi-mediated gene silencing in human cells, here we analyzed the consequences of PDS5 depletion for DNA replication. We found that either PDS5A or PDS5B is sufficient for proper cohesin dynamics and that their simultaneous removal increases cohesin's residence time on chromatin and slows down DNA replication. A similar phenotype was observed in WAPL-depleted cells. Cohesin down-regulation restored normal replication fork rates in PDS5-deficient cells, suggesting that chromatin-bound cohesin hinders the advance of the replisome. We further show that PDS5 proteins are required to recruit WRN helicase-interacting protein 1 (WRNIP1), RAD51 recombinase (RAD51), and BRCA2 DNA repair associated (BRCA2) to stalled forks and that in their absence, nascent DNA strands at unprotected forks are degraded by MRE11 homolog double-strand break repair nuclease (MRE11). These findings indicate that PDS5 proteins participate in replication fork protection and also provide insights into how cohesin and its regulators contribute to the response to replication stress, a common feature of cancer cells.American Society for Biochemistry and Molecular Biology (ASBMB)Ministerio de Economía, Industria y Competitividad (España)Unión Europea. Comisión Europea20212021-08-0620202020-01-0320202020-01-03journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfapplication/pdfhttp://hdl.handle.net/20.500.12105/13272reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Atribución-NoComercial-CompartirIgual 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-sa/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/132722026-06-12T12:43:37Z
dc.title.none.fl_str_mv PDS5 proteins are required for proper cohesin dynamics and participate in replication fork protection.
title PDS5 proteins are required for proper cohesin dynamics and participate in replication fork protection.
spellingShingle PDS5 proteins are required for proper cohesin dynamics and participate in replication fork protection.
Morales, Carmen
DNA Replication
ATPases Associated with Diverse Cellular Activities
Animals
BRCA2 Protein
Cell Cycle Proteins
Cells, Cultured
Chromatin
Chromosomal Proteins, Non-Histone
DNA-Binding Proteins
HeLa Cells
Humans
MRE11 Homologue Protein
Mice
Nuclear Proteins
Rad51 Recombinase
Transcription Factors
title_short PDS5 proteins are required for proper cohesin dynamics and participate in replication fork protection.
title_full PDS5 proteins are required for proper cohesin dynamics and participate in replication fork protection.
title_fullStr PDS5 proteins are required for proper cohesin dynamics and participate in replication fork protection.
title_full_unstemmed PDS5 proteins are required for proper cohesin dynamics and participate in replication fork protection.
title_sort PDS5 proteins are required for proper cohesin dynamics and participate in replication fork protection.
dc.creator.none.fl_str_mv Morales, Carmen
Ruiz-Torres, Miguel
Rodríguez-Acebes, Sara
Rodríguez-Corsino, Miriam
Cisneros, David A
Peters, Jan-Michael
Lafarga, Vanesa
Megias Vazquez, Diego
Mendez, Juan
Losada, Ana
author Morales, Carmen
author_facet Morales, Carmen
Ruiz-Torres, Miguel
Rodríguez-Acebes, Sara
Rodríguez-Corsino, Miriam
Cisneros, David A
Peters, Jan-Michael
Lafarga, Vanesa
Megias Vazquez, Diego
Mendez, Juan
Losada, Ana
author_role author
author2 Ruiz-Torres, Miguel
Rodríguez-Acebes, Sara
Rodríguez-Corsino, Miriam
Cisneros, David A
Peters, Jan-Michael
Lafarga, Vanesa
Megias Vazquez, Diego
Mendez, Juan
Losada, Ana
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía, Industria y Competitividad (España)
Unión Europea. Comisión Europea
dc.subject.none.fl_str_mv DNA Replication
ATPases Associated with Diverse Cellular Activities
Animals
BRCA2 Protein
Cell Cycle Proteins
Cells, Cultured
Chromatin
Chromosomal Proteins, Non-Histone
DNA-Binding Proteins
HeLa Cells
Humans
MRE11 Homologue Protein
Mice
Nuclear Proteins
Rad51 Recombinase
Transcription Factors
topic DNA Replication
ATPases Associated with Diverse Cellular Activities
Animals
BRCA2 Protein
Cell Cycle Proteins
Cells, Cultured
Chromatin
Chromosomal Proteins, Non-Histone
DNA-Binding Proteins
HeLa Cells
Humans
MRE11 Homologue Protein
Mice
Nuclear Proteins
Rad51 Recombinase
Transcription Factors
description Cohesin is a chromatin-bound complex that mediates sister chromatid cohesion and facilitates long-range interactions through DNA looping. How the transcription and replication machineries deal with the presence of cohesin on chromatin remains unclear. The dynamic association of cohesin with chromatin depends on WAPL cohesin release factor (WAPL) and on PDS5 cohesin-associated factor (PDS5), which exists in two versions in vertebrate cells, PDS5A and PDS5B. Using genetic deletion in mouse embryo fibroblasts and a combination of CRISPR-mediated gene editing and RNAi-mediated gene silencing in human cells, here we analyzed the consequences of PDS5 depletion for DNA replication. We found that either PDS5A or PDS5B is sufficient for proper cohesin dynamics and that their simultaneous removal increases cohesin's residence time on chromatin and slows down DNA replication. A similar phenotype was observed in WAPL-depleted cells. Cohesin down-regulation restored normal replication fork rates in PDS5-deficient cells, suggesting that chromatin-bound cohesin hinders the advance of the replisome. We further show that PDS5 proteins are required to recruit WRN helicase-interacting protein 1 (WRNIP1), RAD51 recombinase (RAD51), and BRCA2 DNA repair associated (BRCA2) to stalled forks and that in their absence, nascent DNA strands at unprotected forks are degraded by MRE11 homolog double-strand break repair nuclease (MRE11). These findings indicate that PDS5 proteins participate in replication fork protection and also provide insights into how cohesin and its regulators contribute to the response to replication stress, a common feature of cancer cells.
publishDate 2020
dc.date.none.fl_str_mv 2020
2020-01-03
2020
2020-01-03
2021
2021-08-06
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/13272
url http://hdl.handle.net/20.500.12105/13272
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución-NoComercial-CompartirIgual 4.0 Internacional
http://creativecommons.org/licenses/by-nc-sa/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución-NoComercial-CompartirIgual 4.0 Internacional
http://creativecommons.org/licenses/by-nc-sa/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology (ASBMB)
publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology (ASBMB)
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869415019920228352
score 15.811543

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