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R-loops and regulatory changes in chronologically ageing fission yeast cells drive non-random patterns of genome rearrangements

Aberrant repair of DNA double-strand breaks can recombine distant chromosomal breakpoints. Chromosomal rearrangements compromise genome function and are a hallmark of ageing. Rearrangements are challenging to detect in non-dividing cell populations, because they reflect individually rare, heterogene...

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Autores principales: Ellis, David A., Reyes-Martín, Félix, Rodríguez-López, María, Cotobal, Cristina, Sun, Xi-Ming, Saintain, Quentin, Jeffares, Daniel C., Marguerat, Samuel, Tallada, Víctor A., Bähler, Jürg
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437301/
https://www.ncbi.nlm.nih.gov/pubmed/34464389
http://dx.doi.org/10.1371/journal.pgen.1009784
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author Ellis, David A.
Reyes-Martín, Félix
Rodríguez-López, María
Cotobal, Cristina
Sun, Xi-Ming
Saintain, Quentin
Jeffares, Daniel C.
Marguerat, Samuel
Tallada, Víctor A.
Bähler, Jürg
author_facet Ellis, David A.
Reyes-Martín, Félix
Rodríguez-López, María
Cotobal, Cristina
Sun, Xi-Ming
Saintain, Quentin
Jeffares, Daniel C.
Marguerat, Samuel
Tallada, Víctor A.
Bähler, Jürg
author_sort Ellis, David A.
collection PubMed
description Aberrant repair of DNA double-strand breaks can recombine distant chromosomal breakpoints. Chromosomal rearrangements compromise genome function and are a hallmark of ageing. Rearrangements are challenging to detect in non-dividing cell populations, because they reflect individually rare, heterogeneous events. The genomic distribution of de novo rearrangements in non-dividing cells, and their dynamics during ageing, remain therefore poorly characterized. Studies of genomic instability during ageing have focussed on mitochondrial DNA, small genetic variants, or proliferating cells. To characterize genome rearrangements during cellular ageing in non-dividing cells, we interrogated a single diagnostic measure, DNA breakpoint junctions, using Schizosaccharomyces pombe as a model system. Aberrant DNA junctions that accumulated with age were associated with microhomology sequences and R-loops. Global hotspots for age-associated breakpoint formation were evident near telomeric genes and linked to remote breakpoints elsewhere in the genome, including the mitochondrial chromosome. Formation of breakpoint junctions at global hotspots was inhibited by the Sir2 histone deacetylase and might be triggered by an age-dependent de-repression of chromatin silencing. An unexpected mechanism of genomic instability may cause more local hotspots: age-associated reduction in an RNA-binding protein triggering R-loops at target loci. This result suggests that biological processes other than transcription or replication can drive genome rearrangements. Notably, we detected similar signatures of genome rearrangements that accumulated in old brain cells of humans. These findings provide insights into the unique patterns and possible mechanisms of genome rearrangements in non-dividing cells, which can be promoted by ageing-related changes in gene-regulatory proteins.
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spelling pubmed-84373012021-09-14 R-loops and regulatory changes in chronologically ageing fission yeast cells drive non-random patterns of genome rearrangements Ellis, David A. Reyes-Martín, Félix Rodríguez-López, María Cotobal, Cristina Sun, Xi-Ming Saintain, Quentin Jeffares, Daniel C. Marguerat, Samuel Tallada, Víctor A. Bähler, Jürg PLoS Genet Research Article Aberrant repair of DNA double-strand breaks can recombine distant chromosomal breakpoints. Chromosomal rearrangements compromise genome function and are a hallmark of ageing. Rearrangements are challenging to detect in non-dividing cell populations, because they reflect individually rare, heterogeneous events. The genomic distribution of de novo rearrangements in non-dividing cells, and their dynamics during ageing, remain therefore poorly characterized. Studies of genomic instability during ageing have focussed on mitochondrial DNA, small genetic variants, or proliferating cells. To characterize genome rearrangements during cellular ageing in non-dividing cells, we interrogated a single diagnostic measure, DNA breakpoint junctions, using Schizosaccharomyces pombe as a model system. Aberrant DNA junctions that accumulated with age were associated with microhomology sequences and R-loops. Global hotspots for age-associated breakpoint formation were evident near telomeric genes and linked to remote breakpoints elsewhere in the genome, including the mitochondrial chromosome. Formation of breakpoint junctions at global hotspots was inhibited by the Sir2 histone deacetylase and might be triggered by an age-dependent de-repression of chromatin silencing. An unexpected mechanism of genomic instability may cause more local hotspots: age-associated reduction in an RNA-binding protein triggering R-loops at target loci. This result suggests that biological processes other than transcription or replication can drive genome rearrangements. Notably, we detected similar signatures of genome rearrangements that accumulated in old brain cells of humans. These findings provide insights into the unique patterns and possible mechanisms of genome rearrangements in non-dividing cells, which can be promoted by ageing-related changes in gene-regulatory proteins. Public Library of Science 2021-08-31 /pmc/articles/PMC8437301/ /pubmed/34464389 http://dx.doi.org/10.1371/journal.pgen.1009784 Text en © 2021 Ellis et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Ellis, David A.
Reyes-Martín, Félix
Rodríguez-López, María
Cotobal, Cristina
Sun, Xi-Ming
Saintain, Quentin
Jeffares, Daniel C.
Marguerat, Samuel
Tallada, Víctor A.
Bähler, Jürg
R-loops and regulatory changes in chronologically ageing fission yeast cells drive non-random patterns of genome rearrangements
title R-loops and regulatory changes in chronologically ageing fission yeast cells drive non-random patterns of genome rearrangements
title_full R-loops and regulatory changes in chronologically ageing fission yeast cells drive non-random patterns of genome rearrangements
title_fullStr R-loops and regulatory changes in chronologically ageing fission yeast cells drive non-random patterns of genome rearrangements
title_full_unstemmed R-loops and regulatory changes in chronologically ageing fission yeast cells drive non-random patterns of genome rearrangements
title_short R-loops and regulatory changes in chronologically ageing fission yeast cells drive non-random patterns of genome rearrangements
title_sort r-loops and regulatory changes in chronologically ageing fission yeast cells drive non-random patterns of genome rearrangements
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437301/
https://www.ncbi.nlm.nih.gov/pubmed/34464389
http://dx.doi.org/10.1371/journal.pgen.1009784
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