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:	David A Ellis, Félix Reyes-Martín, María Rodríguez-López, Cristina Cotobal, Xi-Ming Sun, Quentin Saintain, Daniel C Jeffares, Samuel Marguerat, Víctor A Tallada, Jürg Bähler
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/8b1f6da4c8ba46cd8aa5d831906597a2
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spelling	oai:doaj.org-article:8b1f6da4c8ba46cd8aa5d831906597a22021-12-02T20:02:49ZR-loops and regulatory changes in chronologically ageing fission yeast cells drive non-random patterns of genome rearrangements.1553-73901553-740410.1371/journal.pgen.1009784https://doaj.org/article/8b1f6da4c8ba46cd8aa5d831906597a22021-08-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009784https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Aberrant 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.David A EllisFélix Reyes-MartínMaría Rodríguez-LópezCristina CotobalXi-Ming SunQuentin SaintainDaniel C JeffaresSamuel MargueratVíctor A TalladaJürg BählerPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 8, p e1009784 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 David A Ellis Félix Reyes-Martín María Rodríguez-López Cristina Cotobal Xi-Ming Sun Quentin Saintain Daniel C Jeffares Samuel Marguerat Víctor A Tallada Jürg Bähler R-loops and regulatory changes in chronologically ageing fission yeast cells drive non-random patterns of genome rearrangements.
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.
format	article
author	David A Ellis Félix Reyes-Martín María Rodríguez-López Cristina Cotobal Xi-Ming Sun Quentin Saintain Daniel C Jeffares Samuel Marguerat Víctor A Tallada Jürg Bähler
author_facet	David A Ellis Félix Reyes-Martín María Rodríguez-López Cristina Cotobal Xi-Ming Sun Quentin Saintain Daniel C Jeffares Samuel Marguerat Víctor A Tallada Jürg Bähler
author_sort	David A Ellis
title	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_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_sort	r-loops and regulatory changes in chronologically ageing fission yeast cells drive non-random patterns of genome rearrangements.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/8b1f6da4c8ba46cd8aa5d831906597a2
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R-loops and regulatory changes in chronologically ageing fission yeast cells drive non-random patterns of genome rearrangements.

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