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Multi-step processing of replication stress-derived nascent strand DNA gaps by MRE11 and EXO1 nucleases

Accumulation of single stranded DNA (ssDNA) gaps in the nascent strand during DNA replication has been associated with cytotoxicity and hypersensitivity to genotoxic stress, particularly upon inactivation of the BRCA tumor suppressor pathway. However, how ssDNA gaps contribute to genotoxicity is not...

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Autores principales: Hale, Anastasia, Dhoonmoon, Ashna, Straka, Joshua, Nicolae, Claudia M., Moldovan, George-Lucian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10560291/
https://www.ncbi.nlm.nih.gov/pubmed/37805499
http://dx.doi.org/10.1038/s41467-023-42011-0
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author Hale, Anastasia
Dhoonmoon, Ashna
Straka, Joshua
Nicolae, Claudia M.
Moldovan, George-Lucian
author_facet Hale, Anastasia
Dhoonmoon, Ashna
Straka, Joshua
Nicolae, Claudia M.
Moldovan, George-Lucian
author_sort Hale, Anastasia
collection PubMed
description Accumulation of single stranded DNA (ssDNA) gaps in the nascent strand during DNA replication has been associated with cytotoxicity and hypersensitivity to genotoxic stress, particularly upon inactivation of the BRCA tumor suppressor pathway. However, how ssDNA gaps contribute to genotoxicity is not well understood. Here, we describe a multi-step nucleolytic processing of replication stress-induced ssDNA gaps which converts them into cytotoxic double stranded DNA breaks (DSBs). We show that ssDNA gaps are extended bidirectionally by MRE11 in the 3’−5’ direction and by EXO1 in the 5’−3’ direction, in a process which is suppressed by the BRCA pathway. Subsequently, the parental strand at the ssDNA gap is cleaved by the MRE11 endonuclease generating a double strand break. We also show that exposure to bisphenol A (BPA) and diethylhexyl phthalate (DEHP), which are widespread environmental contaminants due to their use in plastics manufacturing, causes nascent strand ssDNA gaps during replication. These gaps are processed through the same mechanism described above to generate DSBs. Our work sheds light on both the relevance of ssDNA gaps as major determinants of genomic instability, as well as the mechanism through which they are processed to generate genomic instability and cytotoxicity.
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spelling pubmed-105602912023-10-09 Multi-step processing of replication stress-derived nascent strand DNA gaps by MRE11 and EXO1 nucleases Hale, Anastasia Dhoonmoon, Ashna Straka, Joshua Nicolae, Claudia M. Moldovan, George-Lucian Nat Commun Article Accumulation of single stranded DNA (ssDNA) gaps in the nascent strand during DNA replication has been associated with cytotoxicity and hypersensitivity to genotoxic stress, particularly upon inactivation of the BRCA tumor suppressor pathway. However, how ssDNA gaps contribute to genotoxicity is not well understood. Here, we describe a multi-step nucleolytic processing of replication stress-induced ssDNA gaps which converts them into cytotoxic double stranded DNA breaks (DSBs). We show that ssDNA gaps are extended bidirectionally by MRE11 in the 3’−5’ direction and by EXO1 in the 5’−3’ direction, in a process which is suppressed by the BRCA pathway. Subsequently, the parental strand at the ssDNA gap is cleaved by the MRE11 endonuclease generating a double strand break. We also show that exposure to bisphenol A (BPA) and diethylhexyl phthalate (DEHP), which are widespread environmental contaminants due to their use in plastics manufacturing, causes nascent strand ssDNA gaps during replication. These gaps are processed through the same mechanism described above to generate DSBs. Our work sheds light on both the relevance of ssDNA gaps as major determinants of genomic instability, as well as the mechanism through which they are processed to generate genomic instability and cytotoxicity. Nature Publishing Group UK 2023-10-07 /pmc/articles/PMC10560291/ /pubmed/37805499 http://dx.doi.org/10.1038/s41467-023-42011-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Hale, Anastasia
Dhoonmoon, Ashna
Straka, Joshua
Nicolae, Claudia M.
Moldovan, George-Lucian
Multi-step processing of replication stress-derived nascent strand DNA gaps by MRE11 and EXO1 nucleases
title Multi-step processing of replication stress-derived nascent strand DNA gaps by MRE11 and EXO1 nucleases
title_full Multi-step processing of replication stress-derived nascent strand DNA gaps by MRE11 and EXO1 nucleases
title_fullStr Multi-step processing of replication stress-derived nascent strand DNA gaps by MRE11 and EXO1 nucleases
title_full_unstemmed Multi-step processing of replication stress-derived nascent strand DNA gaps by MRE11 and EXO1 nucleases
title_short Multi-step processing of replication stress-derived nascent strand DNA gaps by MRE11 and EXO1 nucleases
title_sort multi-step processing of replication stress-derived nascent strand dna gaps by mre11 and exo1 nucleases
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10560291/
https://www.ncbi.nlm.nih.gov/pubmed/37805499
http://dx.doi.org/10.1038/s41467-023-42011-0
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