美国印第安纳大学与普渡大学印第安纳波利斯联合分校（IUPUI）和瑞典优密欧大学（Umea University）最近的一项联合研究显示，有一种细胞用于修复自身DNA断裂的方法（称为断裂诱导复制），比正常合成DNA产生的基因变异要高出2800倍。
要准确无误地传递基因信息必须精确复制DNA。然而DNA复制错误很普遍，细胞已经发展出了几种机制来修复这些错误，变异就是其中一种。从进化适应性来讲，这是有利的，但对于个体生命而言，变异被认为是有害的，可能发展出癌细胞。
研究人员用酵母菌来研究与断裂诱导复制有关的基因突变水平，发现在此过程中基因变异的可能性与DNA的修复位点无关。领导该研究的IUPUI理学院生物学副教授安娜·莫克娃说：“在进行断裂诱导复制时，并不是用一块‘绷带’来修复染色体的断裂，这样碎片就会入侵到其他染色体中并开始复制，很可能导致在错误的时间、错误的地点加入了错误的蛋白质。”
对于是什么原因导致断裂诱导复制比正常复制的错误率要高得多，莫克娃表示，在复制体系中至少有4个变化可能导致一次协同作用风暴，致使在修复过程中产生很高的诱导变异，比如构建DNA的核苷酸会大量集中。“我们认为，尚未找到真正的元凶。”
研究人员还指出，断裂诱导复制所导致的基因突变不会缓慢发生，而是突然暴发，这可能导致癌症。莫克娃说，联合小组将进一步研究断裂诱导复制为什么会给细胞修复带来如此高的变异，并最终找到阻止这些变异产生癌症的方法。（生物谷Bioon.com）
生物谷推荐原文出处：
PLoS Biology, 2011; 9 (2): e1000594 DOI: 10.1371/journal.pbio.1000594
Break-Induced Replication Is Highly Inaccurate
Angela Deem1, Andrea Keszthelyi2, Tiffany Blackgrove1, Alexandra Vayl1, Barbara Coffey1, Ruchi Mathur1, Andrei Chabes2,3, Anna Malkova1*
Abstract
DNA must be synthesized for purposes of genome duplication and DNA repair. While the former is a highly accurate process, short-patch synthesis associated with repair of DNA damage is often error-prone. Break-induced replication (BIR) is a unique cellular process that mimics normal DNA replication in its processivity, rate, and capacity to duplicate hundreds of kilobases, but is initiated at double-strand breaks (DSBs) rather than at replication origins. Here we employed a series of frameshift reporters to measure mutagenesis associated with BIR in Saccharomyces cerevisiae. We demonstrate that BIR DNA synthesis is intrinsically inaccurate over the entire path of the replication fork, as the rate of frameshift mutagenesis during BIR is up to 2,800-fold higher than during normal replication. Importantly, this high rate of mutagenesis was observed not only close to the DSB where BIR is less stable, but also far from the DSB where the BIR replication fork is fast and stabilized. We established that polymerase proofreading and mismatch repair correct BIR errors. Also, dNTP levels were elevated during BIR, and this contributed to BIR-related mutagenesis. We propose that a high level of DNA polymerase errors that is not fully compensated by error-correction mechanisms is largely responsible for mutagenesis during BIR, with Pol δ generating many of the mutagenic errors. We further postulate that activation of BIR in eukaryotic cells may significantly contribute to accumulation of mutations that fuel cancer and evolution.
