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A local ATR-dependent checkpoint pathway is activated by a site-specific replication fork block in human cells

When replication forks encounter DNA lesions that cause polymerase stalling, a checkpoint pathway is activated. The ATR-dependent intra-S checkpoint pathway mediates detection and processing of sites of replication fork stalling to maintain genomic integrity. Several factors involved in the global c...

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Autores principales: Ahmed-Seghir, Sana, Jalan, Manisha, Grimsley, Helen E, Sharma, Aman, Twayana, Shyam, Kosiyatrakul, Settapong T, Thompson, Christopher, Schildkraut, Carl L, Powell, Simon N
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10468204/
https://www.ncbi.nlm.nih.gov/pubmed/37647215
http://dx.doi.org/10.7554/eLife.87357
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author Ahmed-Seghir, Sana
Jalan, Manisha
Grimsley, Helen E
Sharma, Aman
Twayana, Shyam
Kosiyatrakul, Settapong T
Thompson, Christopher
Schildkraut, Carl L
Powell, Simon N
author_facet Ahmed-Seghir, Sana
Jalan, Manisha
Grimsley, Helen E
Sharma, Aman
Twayana, Shyam
Kosiyatrakul, Settapong T
Thompson, Christopher
Schildkraut, Carl L
Powell, Simon N
author_sort Ahmed-Seghir, Sana
collection PubMed
description When replication forks encounter DNA lesions that cause polymerase stalling, a checkpoint pathway is activated. The ATR-dependent intra-S checkpoint pathway mediates detection and processing of sites of replication fork stalling to maintain genomic integrity. Several factors involved in the global checkpoint pathway have been identified, but the response to a single replication fork barrier (RFB) is poorly understood. We utilized the Escherichia coli-based Tus-Ter system in human MCF7 cells and showed that the Tus protein binding to TerB sequences creates an efficient site-specific RFB. The single fork RFB was sufficient to activate a local, but not global, ATR-dependent checkpoint response that leads to phosphorylation and accumulation of DNA damage sensor protein γH2AX, confined locally to within a kilobase of the site of stalling. These data support a model of local management of fork stalling, which allows global replication at sites other than the RFB to continue to progress without delay.
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spelling pubmed-104682042023-08-31 A local ATR-dependent checkpoint pathway is activated by a site-specific replication fork block in human cells Ahmed-Seghir, Sana Jalan, Manisha Grimsley, Helen E Sharma, Aman Twayana, Shyam Kosiyatrakul, Settapong T Thompson, Christopher Schildkraut, Carl L Powell, Simon N eLife Chromosomes and Gene Expression When replication forks encounter DNA lesions that cause polymerase stalling, a checkpoint pathway is activated. The ATR-dependent intra-S checkpoint pathway mediates detection and processing of sites of replication fork stalling to maintain genomic integrity. Several factors involved in the global checkpoint pathway have been identified, but the response to a single replication fork barrier (RFB) is poorly understood. We utilized the Escherichia coli-based Tus-Ter system in human MCF7 cells and showed that the Tus protein binding to TerB sequences creates an efficient site-specific RFB. The single fork RFB was sufficient to activate a local, but not global, ATR-dependent checkpoint response that leads to phosphorylation and accumulation of DNA damage sensor protein γH2AX, confined locally to within a kilobase of the site of stalling. These data support a model of local management of fork stalling, which allows global replication at sites other than the RFB to continue to progress without delay. eLife Sciences Publications, Ltd 2023-08-30 /pmc/articles/PMC10468204/ /pubmed/37647215 http://dx.doi.org/10.7554/eLife.87357 Text en © 2023, Ahmed-Seghir, Jalan et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Chromosomes and Gene Expression
Ahmed-Seghir, Sana
Jalan, Manisha
Grimsley, Helen E
Sharma, Aman
Twayana, Shyam
Kosiyatrakul, Settapong T
Thompson, Christopher
Schildkraut, Carl L
Powell, Simon N
A local ATR-dependent checkpoint pathway is activated by a site-specific replication fork block in human cells
title A local ATR-dependent checkpoint pathway is activated by a site-specific replication fork block in human cells
title_full A local ATR-dependent checkpoint pathway is activated by a site-specific replication fork block in human cells
title_fullStr A local ATR-dependent checkpoint pathway is activated by a site-specific replication fork block in human cells
title_full_unstemmed A local ATR-dependent checkpoint pathway is activated by a site-specific replication fork block in human cells
title_short A local ATR-dependent checkpoint pathway is activated by a site-specific replication fork block in human cells
title_sort local atr-dependent checkpoint pathway is activated by a site-specific replication fork block in human cells
topic Chromosomes and Gene Expression
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10468204/
https://www.ncbi.nlm.nih.gov/pubmed/37647215
http://dx.doi.org/10.7554/eLife.87357
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