Homologous recombination suppresses transgenerational DNA end resection and chromosomal instability in fission yeast
<p>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 sys...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Oxford University Press
2023
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| _version_ | 1826310299178762240 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Pai, C-C |
| collection | OXFORD |
| description | <p>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.</p> |
| first_indexed | 2024-03-07T07:49:54Z |
| format | Journal article |
| id | oxford-uuid:640cc33a-3c9b-43bf-ab45-4bc4db4ae0ca |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:49:54Z |
| publishDate | 2023 |
| publisher | Oxford University Press |
| record_format | dspace |
| spelling | oxford-uuid:640cc33a-3c9b-43bf-ab45-4bc4db4ae0ca2023-07-06T11:24:33ZHomologous recombination suppresses transgenerational DNA end resection and chromosomal instability in fission yeast Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:640cc33a-3c9b-43bf-ab45-4bc4db4ae0caEnglishSymplectic ElementsOxford University Press 2023Pai, C-CDurley, SCCheng, W-CChiang, N-YPeters, JKasparek, TBlaikley, EWee, B-YWalker, CKearsey, SEBuffa, FMurray, JMHumphrey, TC<p>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.</p> |
| spellingShingle | 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 Homologous recombination suppresses transgenerational DNA end resection and chromosomal instability in fission yeast |
| title | Homologous recombination suppresses transgenerational DNA end resection and chromosomal instability in fission yeast |
| title_full | Homologous recombination suppresses transgenerational DNA end resection and chromosomal instability in fission yeast |
| title_fullStr | Homologous recombination suppresses transgenerational DNA end resection and chromosomal instability in fission yeast |
| title_full_unstemmed | Homologous recombination suppresses transgenerational DNA end resection and chromosomal instability in fission yeast |
| title_short | Homologous recombination suppresses transgenerational DNA end resection and chromosomal instability in fission yeast |
| title_sort | homologous recombination suppresses transgenerational dna end resection and chromosomal instability in fission yeast |
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