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R-loop-induced irreparable DNA damage evades checkpoint detection in the C. elegans germline

Accumulation of DNA–RNA hybrids in the form of R-loops can result in replication–transcription conflict that leads to the formation of DNA double strand breaks (DSBs). Using null mutants for the two Caenorhabditis elegans genes encoding for RNaseH1 and RNaseH2, we identify novel effects of R-loop ac...

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Autores principales: Hicks, Tara, Koury, Emily, McCabe, Caleb, Williams, Cameron, Crahan, Caroline, Smolikove, Sarit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9371901/
https://www.ncbi.nlm.nih.gov/pubmed/35871299
http://dx.doi.org/10.1093/nar/gkac621
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author Hicks, Tara
Koury, Emily
McCabe, Caleb
Williams, Cameron
Crahan, Caroline
Smolikove, Sarit
author_facet Hicks, Tara
Koury, Emily
McCabe, Caleb
Williams, Cameron
Crahan, Caroline
Smolikove, Sarit
author_sort Hicks, Tara
collection PubMed
description Accumulation of DNA–RNA hybrids in the form of R-loops can result in replication–transcription conflict that leads to the formation of DNA double strand breaks (DSBs). Using null mutants for the two Caenorhabditis elegans genes encoding for RNaseH1 and RNaseH2, we identify novel effects of R-loop accumulation in the germline. R-loop accumulation leads, as expected, to replication stress, followed by the formation of DSBs. A subset of these DSBs are irreparable. However, unlike irreparable DSBs generated in other systems, which trigger permanent cell cycle arrest, germline irreparable DSBs are propagated to oocytes. Despite DNA damage checkpoint activation in the stem cell niche, the signaling cannot be sustained and nuclei with irreparable DNA damage progress into meiosis. Moreover, unlike other forms of DNA damage that increase germline apoptosis, R-loop-generated DSBs remain undetected by the apoptotic checkpoint. This coincides with attenuation of ATM/ATR signaling in mid-to-late meiotic prophase I. These data altogether indicate that in the germline, DSBs that are generated by R-loops can lead to irreparable DSBs that evade cellular machineries designed for damage recognition. These studies implicate germline R-loops as an especially dangerous driver of germline mutagenesis.
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spelling pubmed-93719012022-08-12 R-loop-induced irreparable DNA damage evades checkpoint detection in the C. elegans germline Hicks, Tara Koury, Emily McCabe, Caleb Williams, Cameron Crahan, Caroline Smolikove, Sarit Nucleic Acids Res Genome Integrity, Repair and Replication Accumulation of DNA–RNA hybrids in the form of R-loops can result in replication–transcription conflict that leads to the formation of DNA double strand breaks (DSBs). Using null mutants for the two Caenorhabditis elegans genes encoding for RNaseH1 and RNaseH2, we identify novel effects of R-loop accumulation in the germline. R-loop accumulation leads, as expected, to replication stress, followed by the formation of DSBs. A subset of these DSBs are irreparable. However, unlike irreparable DSBs generated in other systems, which trigger permanent cell cycle arrest, germline irreparable DSBs are propagated to oocytes. Despite DNA damage checkpoint activation in the stem cell niche, the signaling cannot be sustained and nuclei with irreparable DNA damage progress into meiosis. Moreover, unlike other forms of DNA damage that increase germline apoptosis, R-loop-generated DSBs remain undetected by the apoptotic checkpoint. This coincides with attenuation of ATM/ATR signaling in mid-to-late meiotic prophase I. These data altogether indicate that in the germline, DSBs that are generated by R-loops can lead to irreparable DSBs that evade cellular machineries designed for damage recognition. These studies implicate germline R-loops as an especially dangerous driver of germline mutagenesis. Oxford University Press 2022-07-25 /pmc/articles/PMC9371901/ /pubmed/35871299 http://dx.doi.org/10.1093/nar/gkac621 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Genome Integrity, Repair and Replication
Hicks, Tara
Koury, Emily
McCabe, Caleb
Williams, Cameron
Crahan, Caroline
Smolikove, Sarit
R-loop-induced irreparable DNA damage evades checkpoint detection in the C. elegans germline
title R-loop-induced irreparable DNA damage evades checkpoint detection in the C. elegans germline
title_full R-loop-induced irreparable DNA damage evades checkpoint detection in the C. elegans germline
title_fullStr R-loop-induced irreparable DNA damage evades checkpoint detection in the C. elegans germline
title_full_unstemmed R-loop-induced irreparable DNA damage evades checkpoint detection in the C. elegans germline
title_short R-loop-induced irreparable DNA damage evades checkpoint detection in the C. elegans germline
title_sort r-loop-induced irreparable dna damage evades checkpoint detection in the c. elegans germline
topic Genome Integrity, Repair and Replication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9371901/
https://www.ncbi.nlm.nih.gov/pubmed/35871299
http://dx.doi.org/10.1093/nar/gkac621
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