MRC Oxford Institute for Radiation Oncology & Biology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
Department of Biology, University of Oxford, Zoology Research and Administration Building, Mansfield Road, Oxford OX1 3SZ, UK.
Nucleic Acids Res. 2023 Apr 24;51(7):3205-3222. doi: 10.1093/nar/gkad160.
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.
染色体不稳定性（CIN）驱动细胞间异质性，并导致遗传疾病的发生，包括癌症。同源重组（HR）受损已被认为是 CIN 的主要驱动因素，但潜在机制尚不清楚。使用裂殖酵母模型系统，我们确立了 HR 基因在抑制 DNA 双链断裂（DSB）诱导的 CIN 中的共同作用。此外，我们表明，源自 HR 修复失败或端粒丢失的未修复单端 DSB 是广泛 CIN 的强大驱动因素。携带单端 DSB 的遗传染色体经历多次 DNA 复制和端粒之间的广泛末端处理，这些循环是通过 Cullin 3 介导的 Chk1 丢失和检查点适应来实现的。随后，携带单端 DSB 的不稳定染色体的继续传播，直到跨代末端切除导致单链着丝粒重复的回折倒位，并导致稳定的染色体重排，通常是等臂染色体，或染色体丢失。这些发现揭示了 HR 基因抑制 CIN 的机制，以及在有丝分裂分裂中持续存在的 DNA 断裂如何在产生的后代中传播细胞间异质性。
