Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710.
University Program in Genetics and Genomics, Duke University Medical Center, Durham, North Carolina 27710.
Genetics. 2018 Jun;209(2):425-438. doi: 10.1534/genetics.118.300950. Epub 2018 Apr 2.
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.
在许多生物体中，端粒序列除了位于染色体末端的通常位置外，还可以位于染色体内部。在人类中，这种内部端粒序列（ITS）与肿瘤细胞中的易位断点以及染色体脆性位点（对 DNA 复制受到干扰时断裂的染色体区域）非随机相关。我们之前表明，酵母中的 ITS 产生了几种不同类型的不稳定性，包括末端反转（ITS 与“真正”染色体端粒之间的重组）和 ITS 附近 DNA 序列中的点突变。在当前的研究中，我们检查了这些事件的遗传控制。我们表明，末端反转是在 ITS 内双链 DNA 断裂形成后，通过 DNA 修复的单链退火途径发生的。ITS 诱导的点突变需要易错 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，而是可能是由易错的单链 DNA 缺口修复或在没有 DNA 损伤的情况下 DNA 聚合酶 ζ 的募集导致的。
