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

• Published in: PLoS genetics Vol. 17; no. 8; p. e1009784
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 31.08.2021; Public Library of Science (PLoS)
• Subjects: Age; Aging; Aging - genetics; Biology and Life Sciences; Brain; Breakpoints; Chromatin; Chromosome Aberrations; Chromosome Breakpoints; Chromosome rearrangements; Chromosomes; DNA Breaks, Double-Stranded; DNA damage; DNA repair; Gene Rearrangement - genetics; Gene regulation; Genetic aspects; Genetic diversity; Genetic regulation; Genetic research; Genomes; Genomic instability; Genomic Instability - genetics; Genomics - methods; Histone deacetylase; Hot spots; Microbiological research; Mitochondrial DNA; Models, Genetic; Mutation - genetics; Nucleotide sequence; Physiological aspects; Physiology; R-Loop Structures - genetics; R-loops; Regulatory proteins; Research and Analysis Methods; RNA-binding protein; Schizosaccharomyces - genetics; Schizosaccharomyces - metabolism; Schizosaccharomyces pombe Proteins - genetics; Schizosaccharomyces pombe Proteins - metabolism; Signatures; Telomere - genetics; Transcription; Transcription factors; Yeast; Yeast fungi; United Kingdom
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1009784

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.