Cascades of genetic instability resulting from compromised break-induced replication.
Cascades of genetic instability resulting from compromised break-induced replication.
复制标题
DOI：
10.1371/journal.pgen.1004119
复制
发表时间：
2014-02
期刊：
影响因子：
4.5
通讯作者：
Malkova A
中科院分区：
文献类型：
--
作者：
Vasan S;Deem A;Ramakrishnan S;Argueso JL;Malkova A
断裂诱导复制 (BIR) 是一种修复双链断裂 (DSB) 的机制，双链断裂仅具有一个可以在基因组中找到同源性的末端。这种情况可能是由于复制叉崩溃或端粒侵蚀造成的。 BIR 经常产生各种遗传不稳定性，包括突变、杂合性丢失、缺失、重复和模板转换，这些都可能导致拷贝数变异 (CNV)。与 BIR 特别相关的基因组重排的一种重要类型是半交换 (HC)，它是由重组染色体部分之间的融合引起的。由于 HC 的形成会产生融合分子以及断裂的染色体片段，因此这些事件可能会高度不稳定。在这里，我们证明了 HC 的形成是由于模板损坏、复制体缺陷或有丝分裂过早开始引起的 BIR 中断所致。此外，我们记录了检查点故障促进 BIR 进入半交叉启动的不稳定级联 (HCC)，类似于先前在人类肿瘤中描述的非相互易位 (NRT) 循环。我们假设 HC 是遗传不稳定的一个潜在来源，其严重后果类似于在包括癌症在内的人类疾病中观察到的后果。维持基因组稳定性对于预防出生缺陷、遗传性疾病和其他疾病（包括癌症）非常重要。双链 DNA 断裂 (DSB) 可能是由于活细胞暴露于电离辐射和各种化学物质而导致的，会威胁基因组的完整性，因此 DSB 修复至关重要。 DSB 修复途径的选择很重要，因为某些途径会带来不稳定的后果。断裂诱导复制 (BIR) 是 DSB 修复的一种机制，通常与可能威胁遗传稳定性的有害事件相关。其中一种有害事件是半交叉 (HC) 的形成，当两条染色体在 BIR 修复融合期间发生物理相互作用时就会发生这种情况。在这里，我们采用基于酵母的系统来揭示促进 HC 形成的遗传因素。我们证明，由于 DNA 合成或检查点控制问题而导致的 BIR 中断会促进 HC。此外，我们还发现，BIR 的破坏会促进半交叉启动级联 (HCC)，从而显着破坏基因组的稳定性，并可能被视为导致人类癌症的非相互易位循环的潜在机制。
Break-induced replication (BIR) is a mechanism to repair double-strand breaks (DSBs) that possess only a single end that can find homology in the genome. This situation can result from the collapse of replication forks or telomere erosion. BIR frequently produces various genetic instabilities including mutations, loss of heterozygosity, deletions, duplications, and template switching that can result in copy-number variations (CNVs). An important type of genomic rearrangement specifically linked to BIR is half-crossovers (HCs), which result from fusions between parts of recombining chromosomes. Because HC formation produces a fused molecule as well as a broken chromosome fragment, these events could be highly destabilizing. Here we demonstrate that HC formation results from the interruption of BIR caused by a damaged template, defective replisome or premature onset of mitosis. Additionally, we document that checkpoint failure promotes channeling of BIR into half-crossover-initiated instability cascades (HCC) that resemble cycles of non-reciprocal translocations (NRTs) previously described in human tumors. We postulate that HCs represent a potent source of genetic destabilization with significant consequences that mimic those observed in human diseases, including cancer. Maintaining genomic stability is important to prevent birth defects, genetic disorders and other diseases, including cancer. Double-strand DNA breaks (DSBs), which can result from exposure of living cells to ionizing radiation and various chemicals, threaten genomic integrity, thus making DSB repair essential. The choice of DSB repair pathway is important because some pathways confer destabilizing consequences. Break-induced replication (BIR) is a mechanism of DSB repair that is often associated with deleterious events that can threaten genetic stability. One such deleterious event is the formation of half-crossovers (HCs), which occurs when two chromosomes physically interacting during BIR repair fuse. Here we employed a yeast-based system to unravel the genetic factors promoting HC formation. We demonstrate that the interruption of BIR due to problems in DNA synthesis or checkpoint control, promote HCs. Additionally, we document that disruption of BIR promotes half-crossover-initiated cascades (HCC) that can significantly destabilize the genome and could be accounted as a potential mechanism responsible for cycles of non-reciprocal translocations contributing to cancer in humans.
登录
查看更多内容
影响因子：
4.5
作者：
Chung WH;Zhu Z;Papusha A;Malkova A;Ira G
通讯作者：
Ira G
影响因子：
64.5
作者：
Holmes, AM;Haber, JE
通讯作者：
Haber, JE
DOI：
10.1016/j.mrfmmm.2008.07.013
发表时间：
2008-10-14
影响因子：
2.3
作者：
Downing, Brandon;Morgan, Rachel;Malkova, Anna
通讯作者：
Malkova, Anna
影响因子：
10.5
作者：
Lydeard, John R.;Lipkin-Moore, Zachary;Haber, James E.
通讯作者：
Haber, James E.
DOI：
10.4161/cc.7.19.6720
发表时间：
2008-10
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Baranovskiy AG;Babayeva ND;Liston VG;Rogozin IB;Koonin EV;Pavlov YI;Vassylyev DG;Tahirov TH
通讯作者：
Tahirov TH