A Polymerase Theta-dependent repair pathway suppresses extensive genomic instability at endogenous G4 DNA sites
A Polymerase Theta-dependent repair pathway suppresses extensive genomic instability at endogenous G4 DNA sites
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DOI：
10.1038/ncomms4216
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发表时间：
2014-02-01
影响因子：
16.6
通讯作者：
Tijsterman, Marcel
中科院分区：
文献类型：
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作者：
Koole, Wouter;van Schendel, Robin;Tijsterman, Marcel
基因组包含许多本质上难以复制的序列。例如，串联鸟嘌呤的片段具有采用稳定的G-四链体结构的潜力，这易于引起基因组改变。在这里，我们描述了秀丽隐杆线虫中G4 DNA诱导的突变，并确定了一种非经典的DNA断裂修复机制，该机制产生缺失，其特征是尺寸分布极其狭窄、接头处恰好一个核苷酸的同源性最小以及偶尔存在模板插入。这种典型的突变谱完全依赖于A家族聚合酶Theta，其缺失导致G4基序周围序列的严重丢失。θ介导的末端连接优于非同源末端连接和同源重组，并且以小缺失为代价防止复制叉屏障处的基因组破坏。G4 DNA诱导的缺失也表现在野生型C. elegans，表明在进化过程中这一途径的保护作用。
Genomes contain many sequences that are intrinsically difficult to replicate. Tracts of tandem guanines, for instance, have the potential to adopt stable G-quadruplex structures, which are prone to cause genome alterations. Here we describe G4 DNA-induced mutagenesis in Caenorhabditis elegans and identify a non-canonical DNA break repair mechanism that generates deletions characterized by an extremely narrow size distribution, minimal homology of exactly one nucleotide at the junctions, and by the occasional presence of templated insertions. This typical mutation profile is fully dependent on the A-family polymerase Theta, the absence of which leads to profound loss of sequences surrounding G4 motifs. Theta-mediated end-joining prevails over non- homologous end joining and homologous recombination and prevents genomic havoc at replication fork barriers at the expense of small deletions. G4 DNA-induced deletions also manifest in the genomes of wild isolates of C. elegans, indicating a protective role for this pathway during evolution.