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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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Formato: | Texto |
Lenguaje: | English |
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Oxford University Press
2011
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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. |
format | Text |
id | pubmed-3074140 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
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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