Genetic Control of Genomic Alterations Induced in Yeast by Interstitial Telomeric Sequences.
Genetic Control of Genomic Alterations Induced in Yeast by Interstitial Telomeric Sequences.
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DOI：
10.1534/genetics.118.300950
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发表时间：
2018-06
期刊：
影响因子：
3.3
通讯作者：
Petes T
中科院分区：
文献类型：
--
作者：
Moore A;Dominska M;Greenwell P;Aksenova AY;Mirkin S;Petes T
在许多生物体中，除了通常位于染色体末端的位置外，端粒序列还可以位于染色体内部。在人类中，这种间质端粒序列（ITSs）与肿瘤细胞中的易位断点和染色体脆弱位点（染色体上因DNA复制紊乱而断裂的区域）非随机相关。我们之前的研究表明，酵母中的ITS产生了几种不同类型的不稳定性，包括末端倒置（ITS与“真”染色体端粒之间的重组）和ITS附近DNA序列的点突变。在目前的研究中，我们研究了这些事件的遗传控制。我们发现，在ITS内形成双链DNA断裂后，末端反转通过DNA修复的单链退火途径发生。ITS诱导的点突变需要易出错的DNA聚合酶ζ。与末端反转不同，这些事件不是由双链DNA断裂引发的，而是可能由单链DNA间隙的错误修复或DNA聚合酶ζ在没有DNA损伤的情况下的募集引起的。
In many organisms, telomeric sequences can be located internally on the chromosome in addition to their usual positions at the ends of the chromosome. In humans, such interstitial telomeric sequences (ITSs) are nonrandomly associated with translocation breakpoints in tumor cells and with chromosome fragile sites (regions of the chromosome that break in response to perturbed DNA replication). We previously showed that ITSs in yeast generated several different types of instability, including terminal inversions (recombination between the ITS and the “true” chromosome telomere) and point mutations in DNA sequences adjacent to the ITS. In the current study, we examine the genetic control of these events. We show that the terminal inversions occur by the single-strand annealing pathway of DNA repair following the formation of a double-stranded DNA break within the ITS. The point mutations induced by the ITS require the error-prone DNA polymerase ζ. Unlike the terminal inversions, these events are not initiated by a double-stranded DNA break, but likely result from the error-prone repair of a single-stranded DNA gap or recruitment of DNA polymerase ζ in the absence of DNA damage.