Mre11-Sae2 and RPA Collaborate to Prevent Palindromic Gene Amplification.
Mre11-Sae2 and RPA Collaborate to Prevent Palindromic Gene Amplification.
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DOI：
10.1016/j.molcel.2015.09.027
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发表时间：
2015-11-05
期刊：
影响因子：
16
通讯作者：
Symington LS
中科院分区：
文献类型：
--
作者：
Deng SK;Yin Y;Petes TD;Symington LS
DNA双链断裂上的折叠启动是一种启动回文基因扩增的机制，这是癌细胞的一个共同特征。在这里，我们展示了小的(5-9个碱基)反向重复序列驱动大的回文重复的形成，这是从缺乏Sae2或Mre11核酸酶的酵母细胞中恢复的主要类型的染色体重排。RPA功能障碍使SAE2或Mre11核酸酶缺陷细胞的回文复制频率增加约1000倍，这与链内退火创建发夹状染色体一致，该染色体随后被复制形成双着丝粒等染色体。回文复制经常与重复序列和端粒包围的第二染色体区域的复制有关，这表明双着丝粒染色体的断裂和修复是通过分散的重复序列之间的重组获得端粒。我们认为单链DNA中的二级结构是基因组不稳定性的有力启动者，RPA和Mre11-Sae2分别在阻止它们的形成和繁殖方面发挥着重要作用。
Foldback priming at DNA double-stranded breaks is one mechanism proposed to initiate palindromic gene amplification, a common feature of cancer cells. Here we show small (5–9 bp) inverted repeats drive the formation of large palindromic duplications, the major class of chromosomal rearrangements recovered from yeast cells lacking Sae2 or the Mre11 nuclease. RPA dysfunction increased the frequency of palindromic duplications in Sae2 or Mre11 nuclease-deficient cells by ~1000-fold, consistent with intra-strand annealing to create a hairpin-capped chromosome that is subsequently replicated to form a dicentric isochromosome. The palindromic duplications were frequently associated with duplication of a second chromosome region bounded by a repeated sequence and a telomere, suggesting the dicentric chromosome breaks and repairs by recombination between dispersed repeats to acquire a telomere. We propose secondary structures within single-stranded DNA are potent instigators of genome instability, and RPA and Mre11-Sae2 play important roles in preventing their formation and propagation, respectively.