美國印第安納大學(xué)與普渡大學(xué)印第安納波利斯聯(lián)合分校（IUPUI）和瑞典優(yōu)密歐大學(xué)（Umea University）最近的一項(xiàng)聯(lián)合研究顯示,，有一種細(xì)胞用于修復(fù)自身DNA斷裂的方法（稱為斷裂誘導(dǎo)復(fù)制），比正常合成DNA產(chǎn)生的基因變異要高出2800倍,。
要準(zhǔn)確無誤地傳遞基因信息必須精確復(fù)制DNA,。然而DNA復(fù)制錯(cuò)誤很普遍，細(xì)胞已經(jīng)發(fā)展出了幾種機(jī)制來修復(fù)這些錯(cuò)誤,，變異就是其中一種,。從進(jìn)化適應(yīng)性來講，這是有利的,，但對于個(gè)體生命而言,，變異被認(rèn)為是有害的，可能發(fā)展出癌細(xì)胞,。
研究人員用酵母菌來研究與斷裂誘導(dǎo)復(fù)制有關(guān)的基因突變水平,，發(fā)現(xiàn)在此過程中基因變異的可能性與DNA的修復(fù)位點(diǎn)無關(guān)。領(lǐng)導(dǎo)該研究的IUPUI理學(xué)院生物學(xué)副教授安娜·莫克娃說：“在進(jìn)行斷裂誘導(dǎo)復(fù)制時(shí),，并不是用一塊‘繃帶’來修復(fù)染色體的斷裂,，這樣碎片就會入侵到其他染色體中并開始復(fù)制，很可能導(dǎo)致在錯(cuò)誤的時(shí)間,、錯(cuò)誤的地點(diǎn)加入了錯(cuò)誤的蛋白質(zhì),。”
對于是什么原因?qū)е聰嗔颜T導(dǎo)復(fù)制比正常復(fù)制的錯(cuò)誤率要高得多，莫克娃表示,，在復(fù)制體系中至少有4個(gè)變化可能導(dǎo)致一次協(xié)同作用風(fēng)暴，致使在修復(fù)過程中產(chǎn)生很高的誘導(dǎo)變異,，比如構(gòu)建DNA的核苷酸會大量集中,。“我們認(rèn)為，尚未找到真正的元兇,。”
研究人員還指出,，斷裂誘導(dǎo)復(fù)制所導(dǎo)致的基因突變不會緩慢發(fā)生，而是突然暴發(fā),，這可能導(dǎo)致癌癥,。莫克娃說，聯(lián)合小組將進(jìn)一步研究斷裂誘導(dǎo)復(fù)制為什么會給細(xì)胞修復(fù)帶來如此高的變異,，并最終找到阻止這些變異產(chǎn)生癌癥的方法,。（生物谷Bioon.com）
生物谷推薦原文出處：
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.
