Homologous recombination suppresses transgenerational DNA end resection and chromosomal instability in fission yeast.
Homologous recombination suppresses transgenerational DNA end resection and chromosomal instability in fission yeast.
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DOI：
10.1093/nar/gkad160
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发表时间：
2023-04-24
影响因子：
14.9
通讯作者：
Humphrey, Timothy C.
中科院分区：
文献类型：
--
作者：
Pai, Chen-Chun;Durley, Samuel C.;Cheng, Wei-Chen;Chiang, Nien-Yi;Peters, Jennifer;Kasparek, Torben;Blaikley, Elizabeth;Wee, Boon-Yu;Walker, Carol;Kearsey, Stephen E.;Buffa, Francesca;Murray, Johanne M.;Humphrey, Timothy C.
染色体不稳定(CIN)导致细胞间的异质性，以及包括癌症在内的遗传性疾病的发展。同源重组受损(HR)已被认为是CIN的主要驱动因素，然而，其潜在的机制尚不清楚。利用裂解酵母模型系统，我们建立了HR基因在抑制DNA双链断裂(DSB)诱导的CIN中的共同作用。此外，我们还表明，HR修复失败或端粒丢失导致的未修复的单端DSB是广泛存在的CIN的有力驱动因素。携带单端DSB的遗传染色体在连续的细胞分裂中经历DNA复制和广泛的末端处理周期。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。携带单端DSB的不稳定染色体随后继续繁殖，直到跨代末端切除导致单链着丝粒重复序列的折回倒置和稳定的染色体重排，通常是等染色体，或导致染色体丢失。这些发现揭示了HR基因抑制CIN的机制，以及通过有丝分裂持续的DNA断裂如何在由此产生的后代中传播细胞到细胞的异质性。
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.
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影响因子：
19
作者：
Ceccaldi R;Rondinelli B;D'Andrea AD
通讯作者：
D'Andrea AD
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
5.3
作者：
Du, LL;Nakamura, TM;Russell, P
通讯作者：
Russell, P
影响因子：
21.3
作者：
Chan YW;Fugger K;West SC
通讯作者：
West SC
影响因子：
5.2
作者：
Bonaglia, Maria Clara;Giorda, Roberto;Zuffardi, Orsetta
通讯作者：
Zuffardi, Orsetta