Abstract
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.
Highlights
Cellular processes like transcription and replication can trigger DNA lesions such as doublestrand breaks (DSBs) [1,2,3,4]
Our analyses suggest that similar patterns of chromosomal rearrangements accumulate in brain cells in older humans, raising the possibility that such DNA changes occurring in ageing cells are conserved from yeast to human
DSBs are normally repaired by homologous recombination or by non-homologous end-joining (NHEJ), two pathways which protect chromosomes from aberrant structural variations [6,7,8]
Summary
Cellular processes like transcription and replication can trigger DNA lesions such as doublestrand breaks (DSBs) [1,2,3,4]. E.g. when the regular DNA-repair pathways are compromised, alternate DNA end-joining processes take over, often involving short homologous sequences (microhomologies) that are typically unmasked through DNA-end resection from the DSBs [9,10,11]. Microhomologymediated end-joining (MMEJ) can link chromosomal breakpoints that are normally far apart or even on different chromosomes [12,13]. Such events lead to genome rearrangements such as inversions, duplications, translocations or deletions, which can considerably affect the function of genomes. The patterns of genome rearrangements are shaped by the particular mechanisms of their formation and by the fitness effects they exert on the cell
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