Fragile DNA motifs trigger mutagenesis at distant chromosomal loci in saccharomyces cerevisiae.
Fragile DNA motifs trigger mutagenesis at distant chromosomal loci in saccharomyces cerevisiae.
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DOI：
10.1371/journal.pgen.1003551
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发表时间：
2013-06
期刊：
影响因子：
4.5
通讯作者：
Lobachev KS
中科院分区：
文献类型：
--
作者：
Saini N;Zhang Y;Nishida Y;Sheng Z;Choudhury S;Mieczkowski P;Lobachev KS
能够采用非典型二级结构的DNA序列与人类和模式生物中的染色体重排有关。以前，我们已经表明，长的反向重复序列，形成发夹和十字形结构和三链体形成GAA/TTC重复序列诱导形成双链断裂，触发基因组不稳定的酵母。在这项研究中，我们证明了在两个反向重复和GAA/TTC重复的断裂是由DNA复制缺陷增强。脆性增加与报告基因中突变水平增加相关，报告基因位于距离重复序列两侧8 kb处。突变的增加依赖于反向或GAA/TTC重复序列的存在和跨损伤聚合酶Pol γ的活性。由反向重复序列诱导的突变也需要Sae 2，其打开发夹帽断裂并启动末端切除。重复序列处的断裂量是突变的重要决定因素，因为还发现具有固有增加的脆性的完美回文序列即使在复制熟练的菌株中也会提高突变率。我们推测脆性基序诱导突变的潜在机制涉及断裂染色体中长单链区域的形成，未受损姐妹染色单体的修复入侵，以及使用Pol β的错误DNA合成。这些数据表明，重复介导的断裂通过诱导染色体畸变以及侧翼基因突变对真核基因组完整性构成双重威胁。真核染色体包括易断裂和重排的区域。可以采用非B型DNA二级结构的重复序列通常被发现是诱导重排的原因。在这里，我们证明了反向重复序列和GAA/TTC断裂位点也是点突变的来源，点突变可以传播到距离重复序列很远的基因。值得注意的是，涉及易错合成的断裂修复恢复了反向重复序列，使其成为长期的突变资源。这些结果表明，断裂基序的染色体区域有很高的潜力，结构重排，以及积累核苷酸多态性的趋势。在这些区域增加的遗传变化可能会改变进化尺度上的变化率，并有助于疾病的发展。
DNA sequences capable of adopting non-canonical secondary structures have been associated with gross-chromosomal rearrangements in humans and model organisms. Previously, we have shown that long inverted repeats that form hairpin and cruciform structures and triplex-forming GAA/TTC repeats induce the formation of double-strand breaks which trigger genome instability in yeast. In this study, we demonstrate that breakage at both inverted repeats and GAA/TTC repeats is augmented by defects in DNA replication. Increased fragility is associated with increased mutation levels in the reporter genes located as far as 8 kb from both sides of the repeats. The increase in mutations was dependent on the presence of inverted or GAA/TTC repeats and activity of the translesion polymerase Polζ. Mutagenesis induced by inverted repeats also required Sae2 which opens hairpin-capped breaks and initiates end resection. The amount of breakage at the repeats is an important determinant of mutations as a perfect palindromic sequence with inherently increased fragility was also found to elevate mutation rates even in replication-proficient strains. We hypothesize that the underlying mechanism for mutagenesis induced by fragile motifs involves the formation of long single-stranded regions in the broken chromosome, invasion of the undamaged sister chromatid for repair, and faulty DNA synthesis employing Polζ. These data demonstrate that repeat-mediated breaks pose a dual threat to eukaryotic genome integrity by inducing chromosomal aberrations as well as mutations in flanking genes. Eukaryotic chromosomes include regions that are susceptible for breakage and rearrangements. Repeats that can adopt non-B form DNA secondary structure are often found to be responsible for the induction of rearrangements. Here, we demonstrate that inverted repeats and GAA/TTC breakage sites are also sources of point mutagenesis that can spread to the genes located at long distances from the repeats. Remarkably, repair of the break involving error-prone synthesis restores inverted repeats making them a long-term resource of mutations. These results demonstrate that chromosomal regions with breakage motifs have a high potential for structural rearrangements as well as a tendency to accumulate nucleotide polymorphisms. Increased genetic changes in such regions may alter the rate of changes at the evolutionary scale and contribute to the development of diseases.
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影响因子：
16
作者：
Lengsfeld, Bettina M.;Rattray, Alison J.;Paull, Tanya T.
通讯作者：
Paull, Tanya T.
影响因子：
56.9
作者：
HARRIS, RS;LONGERICH, S;ROSENBERG, SM
通讯作者：
ROSENBERG, SM
影响因子：
64.8
作者：
Berger, Michael F.;Lawrence, Michael S.;Demichelis, Francesca;Drier, Yotam;Cibulskis, Kristian;Sivachenko, Andrey Y.;Sboner, Andrea;Esgueva, Raquel;Pflueger, Dorothee;Sougnez, Carrie;Onofrio, Robert;Carter, Scott L.;Park, Kyung;Habegger, Lukas;Ambrogio, Lauren;Fennell, Timothy;Parkin, Melissa;Saksena, Gordon;Voet, Douglas;Ramos, Alex H.;Pugh, Trevor J.;Wilkinson, Jane;Fisher, Sheila;Winckler, Wendy;Mahan, Scott;Ardlie, Kristin;Baldwin, Jennifer;Simons, Jonathan W.;Kitabayashi, Naoki;MacDonald, Theresa Y.;Kantoff, Philip W.;Chin, Lynda;Gabriel, Stacey B.;Gerstein, Mark B.;Golub, Todd R.;Meyerson, Matthew;Tewari, Ashutosh;Lander, Eric S.;Getz, Gad;Rubin, Mark A.;Garraway, Levi A.
通讯作者：
Garraway, Levi A.
DOI：
10.1126/science.1191125
发表时间：
2010-07-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hicks WM;Kim M;Haber JE
通讯作者：
Haber JE
影响因子：
9.2
作者：
Hirano, Y;Sugimoto, K
通讯作者：
Sugimoto, K