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Publication Detail
Physiological changes during cellular ageing in fission yeast drive non-random patterns of genome rearrangements
  • Publication Type:
    Working discussion paper
  • Authors:
    Ellis D, Reyes-Martin F, Rodriguez-Lopez M, Cotobal Martin C, Jeffares D, Tallada V, Bahler J
  • Publication date:
    17/01/2019
  • Status:
    Published
Abstract
Aberrant repair of DNA double-strand breaks can recombine distant pairs of chromosomal breakpoints. Such chromosomal rearrangements are a hallmark of ageing and markedly compromise genome structure and function. Rearrangements are challenging to detect in genomes of 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 in ageing cells have focused on mitochondrial DNA, small genetic variants, or proliferating cells. To gain a better understanding of genome rearrangements during chronological ageing, we reduced their complexity to a single diagnostic measure, the DNA breakpoint junctions, allowing us to interrogate the changing genomic landscape in non-dividing cells of fission yeast ( Schizosaccharomyces pombe ). Aberrant DNA junctions that accumulated with age were associated with microhomology sequences and gene transcription. We present an unexpected cause of genomic instability, where age-associated reduction in an RNA-binding protein could trigger R-loop formation at target loci. This example suggests that physiological changes in processes un-related to transcription or replication can drive genome rearrangements. We also identified global hotspots for age-associated breakpoint formation, near telomeric genes and binding sites of genome regulators, linked to remote breakpoints on the same or different chromosomes. Notably, we uncovered similar signatures of genome rearrangements that accumulated in old brain cells of humans. These findings provide fresh insights into the unique patterns and potential mechanisms of genome rearrangements in non-dividing cells, which can be triggered by ageing-related changes in gene-regulation proteins.
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