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Nucleases and Co-Factors in DNA Replication Stress Responses
DNA replication stress is a constant threat that cells must manage to proliferate and maintain genome integrity. DNA replication stress responses, a subset of the broader DNA damage response (DDR), operate when the DNA replication machinery (replisome) is blocked or replication forks collapse during...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9534323/ https://www.ncbi.nlm.nih.gov/pubmed/36203968 http://dx.doi.org/10.3390/dna2010006 |
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author | Nickoloff, Jac A. Sharma, Neelam Taylor, Lynn Allen, Sage J. Hromas, Robert |
author_facet | Nickoloff, Jac A. Sharma, Neelam Taylor, Lynn Allen, Sage J. Hromas, Robert |
author_sort | Nickoloff, Jac A. |
collection | PubMed |
description | DNA replication stress is a constant threat that cells must manage to proliferate and maintain genome integrity. DNA replication stress responses, a subset of the broader DNA damage response (DDR), operate when the DNA replication machinery (replisome) is blocked or replication forks collapse during S phase. There are many sources of replication stress, such as DNA lesions caused by endogenous and exogenous agents including commonly used cancer therapeutics, and difficult-to-replicate DNA sequences comprising fragile sites, G-quadraplex DNA, hairpins at trinucleotide repeats, and telomeres. Replication stress is also a consequence of conflicts between opposing transcription and replication, and oncogenic stress which dysregulates replication origin firing and fork progression. Cells initially respond to replication stress by protecting blocked replisomes, but if the offending problem (e.g., DNA damage) is not bypassed or resolved in a timely manner, forks may be cleaved by nucleases, inducing a DNA double-strand break (DSB) and providing a means to accurately restart stalled forks via homologous recombination. However, DSBs pose their own risks to genome stability if left unrepaired or misrepaired. Here we focus on replication stress response systems, comprising DDR signaling, fork protection, and fork processing by nucleases that promote fork repair and restart. Replication stress nucleases include MUS81, EEPD1, Metnase, CtIP, MRE11, EXO1, DNA2-BLM, SLX1-SLX4, XPF-ERCC1-SLX4, Artemis, XPG, and FEN1. Replication stress factors are important in cancer etiology as suppressors of genome instability associated with oncogenic mutations, and as potential cancer therapy targets to enhance the efficacy of chemo- and radiotherapeutics. |
format | Online Article Text |
id | pubmed-9534323 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
record_format | MEDLINE/PubMed |
spelling | pubmed-95343232022-10-05 Nucleases and Co-Factors in DNA Replication Stress Responses Nickoloff, Jac A. Sharma, Neelam Taylor, Lynn Allen, Sage J. Hromas, Robert DNA (Basel) Article DNA replication stress is a constant threat that cells must manage to proliferate and maintain genome integrity. DNA replication stress responses, a subset of the broader DNA damage response (DDR), operate when the DNA replication machinery (replisome) is blocked or replication forks collapse during S phase. There are many sources of replication stress, such as DNA lesions caused by endogenous and exogenous agents including commonly used cancer therapeutics, and difficult-to-replicate DNA sequences comprising fragile sites, G-quadraplex DNA, hairpins at trinucleotide repeats, and telomeres. Replication stress is also a consequence of conflicts between opposing transcription and replication, and oncogenic stress which dysregulates replication origin firing and fork progression. Cells initially respond to replication stress by protecting blocked replisomes, but if the offending problem (e.g., DNA damage) is not bypassed or resolved in a timely manner, forks may be cleaved by nucleases, inducing a DNA double-strand break (DSB) and providing a means to accurately restart stalled forks via homologous recombination. However, DSBs pose their own risks to genome stability if left unrepaired or misrepaired. Here we focus on replication stress response systems, comprising DDR signaling, fork protection, and fork processing by nucleases that promote fork repair and restart. Replication stress nucleases include MUS81, EEPD1, Metnase, CtIP, MRE11, EXO1, DNA2-BLM, SLX1-SLX4, XPF-ERCC1-SLX4, Artemis, XPG, and FEN1. Replication stress factors are important in cancer etiology as suppressors of genome instability associated with oncogenic mutations, and as potential cancer therapy targets to enhance the efficacy of chemo- and radiotherapeutics. 2022-03 2022-03-01 /pmc/articles/PMC9534323/ /pubmed/36203968 http://dx.doi.org/10.3390/dna2010006 Text en https://creativecommons.org/licenses/by/4.0/This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Nickoloff, Jac A. Sharma, Neelam Taylor, Lynn Allen, Sage J. Hromas, Robert Nucleases and Co-Factors in DNA Replication Stress Responses |
title | Nucleases and Co-Factors in DNA Replication Stress Responses |
title_full | Nucleases and Co-Factors in DNA Replication Stress Responses |
title_fullStr | Nucleases and Co-Factors in DNA Replication Stress Responses |
title_full_unstemmed | Nucleases and Co-Factors in DNA Replication Stress Responses |
title_short | Nucleases and Co-Factors in DNA Replication Stress Responses |
title_sort | nucleases and co-factors in dna replication stress responses |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9534323/ https://www.ncbi.nlm.nih.gov/pubmed/36203968 http://dx.doi.org/10.3390/dna2010006 |
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