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Replication fork stalling by bulky DNA damage: localization at active origins and checkpoint modulation

The integrity of the genome is threatened by DNA damage that blocks the progression of replication forks. Little is known about the genomic locations of replication fork stalling, and its determinants and consequences in vivo. Here we show that bulky DNA damaging agents induce localized fork stallin...

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Detalles Bibliográficos
Autores principales: Minca, Eugen C., Kowalski, David
Formato: Texto
Lenguaje:English
Publicado: Oxford University Press 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3074140/
https://www.ncbi.nlm.nih.gov/pubmed/21138968
http://dx.doi.org/10.1093/nar/gkq1215
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author Minca, Eugen C.
Kowalski, David
author_facet Minca, Eugen C.
Kowalski, David
author_sort Minca, Eugen C.
collection PubMed
description The integrity of the genome is threatened by DNA damage that blocks the progression of replication forks. Little is known about the genomic locations of replication fork stalling, and its determinants and consequences in vivo. Here we show that bulky DNA damaging agents induce localized fork stalling at yeast replication origins, and that localized stalling is dependent on proximal origin activity and is modulated by the intra–S–phase checkpoint. Fork stalling preceded the formation of sister chromatid junctions required for bypassing DNA damage. Despite DNA adduct formation, localized fork stalling was abrogated at an origin inactivated by a point mutation and prominent stalling was not detected at naturally-inactive origins in the replicon. The intra–S–phase checkpoint contributed to the high-level of fork stalling at early origins, while checkpoint inactivation led to initiation, localized stalling and chromatid joining at a late origin. Our results indicate that replication forks initially encountering a bulky DNA adduct exhibit a dual nature of stalling: a checkpoint-independent arrest that triggers sister chromatid junction formation, as well as a checkpoint-enhanced arrest at early origins that accompanies the repression of late origin firing. We propose that the initial checkpoint-enhanced arrest reflects events that facilitate fork resolution at subsequent lesions.
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spelling pubmed-30741402011-04-12 Replication fork stalling by bulky DNA damage: localization at active origins and checkpoint modulation Minca, Eugen C. Kowalski, David Nucleic Acids Res Genome Integrity, Repair and Replication The integrity of the genome is threatened by DNA damage that blocks the progression of replication forks. Little is known about the genomic locations of replication fork stalling, and its determinants and consequences in vivo. Here we show that bulky DNA damaging agents induce localized fork stalling at yeast replication origins, and that localized stalling is dependent on proximal origin activity and is modulated by the intra–S–phase checkpoint. Fork stalling preceded the formation of sister chromatid junctions required for bypassing DNA damage. Despite DNA adduct formation, localized fork stalling was abrogated at an origin inactivated by a point mutation and prominent stalling was not detected at naturally-inactive origins in the replicon. The intra–S–phase checkpoint contributed to the high-level of fork stalling at early origins, while checkpoint inactivation led to initiation, localized stalling and chromatid joining at a late origin. Our results indicate that replication forks initially encountering a bulky DNA adduct exhibit a dual nature of stalling: a checkpoint-independent arrest that triggers sister chromatid junction formation, as well as a checkpoint-enhanced arrest at early origins that accompanies the repression of late origin firing. We propose that the initial checkpoint-enhanced arrest reflects events that facilitate fork resolution at subsequent lesions. Oxford University Press 2011-04 2010-12-07 /pmc/articles/PMC3074140/ /pubmed/21138968 http://dx.doi.org/10.1093/nar/gkq1215 Text en © The Author(s) 2010. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/2.5 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Genome Integrity, Repair and Replication
Minca, Eugen C.
Kowalski, David
Replication fork stalling by bulky DNA damage: localization at active origins and checkpoint modulation
title Replication fork stalling by bulky DNA damage: localization at active origins and checkpoint modulation
title_full Replication fork stalling by bulky DNA damage: localization at active origins and checkpoint modulation
title_fullStr Replication fork stalling by bulky DNA damage: localization at active origins and checkpoint modulation
title_full_unstemmed Replication fork stalling by bulky DNA damage: localization at active origins and checkpoint modulation
title_short Replication fork stalling by bulky DNA damage: localization at active origins and checkpoint modulation
title_sort replication fork stalling by bulky dna damage: localization at active origins and checkpoint modulation
topic Genome Integrity, Repair and Replication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3074140/
https://www.ncbi.nlm.nih.gov/pubmed/21138968
http://dx.doi.org/10.1093/nar/gkq1215
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