Failed gene conversion leads to extensive end processing and chromosomal rearrangements in fission yeast
Failed gene conversion leads to extensive end processing and chromosomal rearrangements in fission yeast
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失败的基因转换导致裂殖酵母中广泛的末端加工和染色体重排
作者：
Helen Tinline;Andrew P. Savory;Jason K. Cullen;Anoushka Davé;J. Moss;Wendy L Bridge;S. Marguerat;J. Bähler;J. Ragoussis;R. Mott;Carol A Walker;T. Humphrey
杂合性缺失（洛）是癌症和人类遗传性疾病中的一个致病事件，通常包括多个遗传基因座和整个染色体臂。然而，这种广泛的洛缺失发生的机制，以及它在正常细胞中是如何被抑制的，目前还知之甚少。我们已经开发了一个遗传系统来研究DNA双链断裂（DSB）诱导的广泛洛的机制，并使用非必需的微型染色体Ch16，在裂殖酵母中进行抑制。我们发现广泛的洛缺失是由一种新的断裂诱导的等染色体形成机制引起的。我们的数据支持一个模型，其中来自未修复的DSB的Rqh 1和Exo 1依赖性末端加工导致断裂的染色体臂的去除，并导致断裂诱导的完整臂从着丝粒复制，距离初始病变相当远。这一过程也促进了全基因组拷贝数变异。遗传筛选显示Rhp51、Rhp55、Rhp57和MRN复合物抑制等染色体形成和染色体丢失，这与与同源重组修复失败相关的广泛末端加工导致的这些事件一致。
Loss of heterozygosity (LOH), a causal event in cancer and human genetic diseases, frequently encompasses multiple genetic loci and whole chromosome arms. However, the mechanisms by which such extensive LOH arises, and how it is suppressed in normal cells is poorly understood. We have developed a genetic system to investigate the mechanisms of DNA double‐strand break (DSB)‐induced extensive LOH, and its suppression, using a non‐essential minichromosome, Ch16, in fission yeast. We find extensive LOH to arise from a new break‐induced mechanism of isochromosome formation. Our data support a model in which Rqh1 and Exo1‐dependent end processing from an unrepaired DSB leads to removal of the broken chromosome arm and to break‐induced replication of the intact arm from the centromere, a considerable distance from the initial lesion. This process also promotes genome‐wide copy number variation. A genetic screen revealed Rhp51, Rhp55, Rhp57 and the MRN complex to suppress both isochromosome formation and chromosome loss, in accordance with these events resulting from extensive end processing associated with failed homologous recombination repair.
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影响因子：
3.8
作者：
Myung, K;Kolodner, RD
通讯作者：
Kolodner, RD
影响因子：
16
作者：
Wolner, B;van Komen, S;Peterson, CL
通讯作者：
Peterson, CL
影响因子：
16
作者：
Sugawara, N;Wang, X;Haber, JE
通讯作者：
Haber, JE
染色体断裂诱导的 DNA 复制导致不可逆易位和端粒捕获。
影响因子：
3.3
作者：
Bosco,G;Haber,JE
通讯作者：
Haber,JE
影响因子：
16
作者：
Limbo, Oliver;Chahwan, Charly;Russell, Paul
通讯作者：
Russell, Paul