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

by David A. Ellis, F élix Reyes-Martín, María Rodríguez-López, Cristina Cotobal, Xi-Ming Sun, Quentin Saintain, Daniel C. Jeffares, Samuel Marguerat, Víctor A. Tallada, Jürg Bähler 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, heteroge neous events. The genomic distribution ofde 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, usingSchizosaccharomyces 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 instabi...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research