Human telomeres that contain (CTAGGG)n repeats show replication dependent instability in somatic cells and the male germline.
Human telomeres that contain (CTAGGG)n repeats show replication dependent instability in somatic cells and the male germline.
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DOI：
10.1093/nar/gkp629
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发表时间：
2009-10
影响因子：
14.9
通讯作者：
Royle NJ
中科院分区：
文献类型：
--
作者：
Mendez-Bermudez A;Hills M;Pickett HA;Phan AT;Mergny JL;Riou JF;Royle NJ
一些不同的过程，影响端粒长度的动态已被确定，但影响的因素，位于端粒DNA内的近端的重复的营业额是不明确的。我们已经确定了一个特定的重复类型（CTAGGG），这是一个非常高的突变率（20%每配子）在男性生殖细胞。突变率受（CTAGGG）n阵列的长度和序列均一性的影响。这种水平的不稳定性在其他序列变异重复中没有发现，包括具有相同组成的TCAGGG重复类型。携带（CTAGGG）n阵列的端粒在体细胞中也是高度不稳定的，突变过程导致重复序列的少量增加或丢失，偶尔也会导致整个（CTAGGG）n阵列的缺失。这些序列在体外易于形成四链体，但采用与（TTAGGG）n不同的拓扑结构（见随附文章）。有趣的是，在正常成纤维细胞中，短的（CTAGGG）2寡核苷酸诱导DNA损伤反应（γH2AX灶）与（TTAGGG）2寡核苷酸一样有效，表明它们从端粒募集POT1。此外，体外试验表明，（CTAGGG）n重复序列比（TTAGGG）n或（TCAGGG）n更有效地结合POT1。我们估计7%的人类端粒含有（CTAGGG）n重复序列，当存在时，它们会产生端粒复制过程中可能出现的其他问题。
A number of different processes that impact on telomere length dynamics have been identified but factors that affect the turnover of repeats located proximally within the telomeric DNA are poorly defined. We have identified a particular repeat type (CTAGGG) that is associated with an extraordinarily high mutation rate (20% per gamete) in the male germline. The mutation rate is affected by the length and sequence homogeneity of the (CTAGGG)n array. This level of instability was not seen with other sequence-variant repeats, including the TCAGGG repeat type that has the same composition. Telomeres carrying a (CTAGGG)n array are also highly unstable in somatic cells with the mutation process resulting in small gains or losses of repeats that also occasionally result in the deletion of the whole (CTAGGG)n array. These sequences are prone to quadruplex formation in vitro but adopt a different topology from (TTAGGG)n (see accompanying article). Interestingly, short (CTAGGG)2 oligonucleotides induce a DNA damage response (γH2AX foci) as efficiently as (TTAGGG)2 oligos in normal fibroblast cells, suggesting they recruit POT1 from the telomere. Moreover, in vitro assays show that (CTAGGG)n repeats bind POT1 more efficiently than (TTAGGG)n or (TCAGGG)n. We estimate that 7% of human telomeres contain (CTAGGG)n repeats and when present, they create additional problems that probably arise during telomere replication.
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作者：
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