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

• DOI: 10.1371/journal.pgen.1009784
• Publication Date: 2021-08-31T18:15:48Z
• Authors: David A. Ellis; Félix Reyes-Martín; María Rodríguez-L...; Cristina Cotobal; Xi-Ming Sun; Quentin Saintain; Daniel C. Jeffares; Samuel Marguerat; Víctor A. Tallada; Jürg Bähler
• Keywords: Breakpoint; Chromosomal fragile site

Aberrant repair of DNA double-strand breaks can recombine distant chromosomal breakpoints. Chromosomal rearrangements compromise genome function and are a hallmark ageing. Rearrangements challenging to detect in non-dividing cell populations, because they reflect individually rare, heterogeneous events. The genomic distribution de novo cells, their dynamics during ageing, remain therefore poorly characterized. Studies instability ageing have focussed on mitochondrial DNA, small genetic variants, or proliferating cells. To characterize cellular we interrogated single diagnostic measure, breakpoint junctions, using Schizosaccharomyces pombe as model system. junctions that accumulated with age were associated microhomology sequences R-loops. Global hotspots for age-associated formation evident near telomeric genes linked remote breakpoints elsewhere the genome, including chromosome. Formation at global was inhibited by Sir2 histone deacetylase might be triggered an age-dependent de-repression chromatin silencing. An unexpected mechanism may cause more local hotspots: reduction RNA-binding protein triggering R-loops target loci. This result suggests biological processes other than transcription replication drive rearrangements. Notably, detected similar signatures old brain cells humans. These findings provide insights into unique patterns possible mechanisms which promoted ageing-related changes gene-regulatory proteins.