| Title: |
Homologous recombination suppresses transgenerational DNA end resection and chromosomal instability in fission yeast |
| Authors: |
Pai, C-C; Durley, SC; Cheng, W-C; Chiang, N-Y; Peters, J; Kasparek, T; Blaikley, E; Wee, B-Y; Walker, C; Kearsey, SE; Buffa, F; Murray, JM; Humphrey, TC |
| Publisher Information: |
Oxford University Press |
| Publication Year: |
2023 |
| Collection: |
Oxford University Research Archive (ORA) |
| Description: |
Chromosomal instability (CIN) drives cell-to-cell heterogeneity, and the development of genetic diseases, including cancer. Impaired homologous recombination (HR) has been implicated as a major driver of CIN, however, the underlying mechanism remains unclear. Using a fission yeast model system, we establish a common role for HR genes in suppressing DNA double-strand break (DSB)-induced CIN. Further, we show that an unrepaired single-ended DSB arising from failed HR repair or telomere loss is a potent driver of widespread CIN. Inherited chromosomes carrying a single-ended DSB are subject to cycles of DNA replication and extensive end-processing across successive cell divisions. These cycles are enabled by Cullin 3-mediated Chk1 loss and checkpoint adaptation. Subsequent propagation of unstable chromosomes carrying a single-ended DSB continues until transgenerational end-resection leads to fold-back inversion of single-stranded centromeric repeats and to stable chromosomal rearrangements, typically isochromosomes, or to chromosomal loss. These findings reveal a mechanism by which HR genes suppress CIN and how DNA breaks that persist through mitotic divisions propagate cell-to-cell heterogeneity in the resultant progeny. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
https://doi.org/10.1093/nar/gkad160 |
| DOI: |
10.1093/nar/gkad160 |
| Availability: |
https://doi.org/10.1093/nar/gkad160; https://ora.ox.ac.uk/objects/uuid:640cc33a-3c9b-43bf-ab45-4bc4db4ae0ca |
| Rights: |
info:eu-repo/semantics/openAccess ; CC Attribution (CC BY) |
| Accession Number: |
edsbas.806B9C40 |
| Database: |
BASE |