Telomere extension by telomerase and ALT generates variant repeats by mechanistically distinct processes.
Telomere extension by telomerase and ALT generates variant repeats by mechanistically distinct processes.
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DOI：
10.1093/nar/gkt1117
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发表时间：
2014-02
影响因子：
14.9
通讯作者：
Pickett HA
中科院分区：
文献类型：
--
作者：
Lee M;Hills M;Conomos D;Stutz MD;Dagg RA;Lau LM;Reddel RR;Pickett HA
端粒是染色体上的末端重复 DNA 序列，被认为几乎完全包含六聚体 TTAGGG 重复序列。我们使用全基因组测序，然后在一组致命细胞株和永生细胞系中提取端粒读数，评估了人类细胞中的端粒序列内容。我们在人类细胞中鉴定出多种端粒变异重复序列，并发现证据表明变异重复序列是在端粒酶和 ALT 介导的端粒延长过程中通过机械上不同的过程产生的。端粒酶介导的端粒延伸导致变异重复的有偏差重复合成，这些重复序列在位置 1 和 3 处不同于规范序列，但在位置 2、4、5 或 6 处则不然。这表明端粒酶很可能是一种容易出错的逆转录酶，它会在端粒酶 RNA 模板上的特定位置错误掺入核苷酸。相比之下，使用 ALT 途径的细胞系包含大量的变异重复序列，这些重复序列在细胞系之间差异很大。这与通过重组介导的 DNA 合成模板以随机方式从近端端粒区域扩散到整个端粒的变异重复序列一致。利用任一端粒维持机制的细胞中出现出乎意料的大量变异重复序列表明人类端粒变异序列具有保守作用。
Telomeres are terminal repetitive DNA sequences on chromosomes, and are considered to comprise almost exclusively hexameric TTAGGG repeats. We have evaluated telomere sequence content in human cells using whole-genome sequencing followed by telomere read extraction in a panel of mortal cell strains and immortal cell lines. We identified a wide range of telomere variant repeats in human cells, and found evidence that variant repeats are generated by mechanistically distinct processes during telomerase- and ALT-mediated telomere lengthening. Telomerase-mediated telomere extension resulted in biased repeat synthesis of variant repeats that differed from the canonical sequence at positions 1 and 3, but not at positions 2, 4, 5 or 6. This indicates that telomerase is most likely an error-prone reverse transcriptase that misincorporates nucleotides at specific positions on the telomerase RNA template. In contrast, cell lines that use the ALT pathway contained a large range of variant repeats that varied greatly between lines. This is consistent with variant repeats spreading from proximal telomeric regions throughout telomeres in a stochastic manner by recombination-mediated templating of DNA synthesis. The presence of unexpectedly large numbers of variant repeats in cells utilizing either telomere maintenance mechanism suggests a conserved role for variant sequences at human telomeres.
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影响因子：
14.9
作者：
Cawthon RM
通讯作者：
Cawthon RM
影响因子：
3.3
作者：
Brault ME;Autexier C
通讯作者：
Autexier C
影响因子：
11.4
作者：
BAIRD, DM;JEFFREYS, AJ;ROYLE, NJ
通讯作者：
ROYLE, NJ
影响因子：
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作者：
Broccoli, D;Smogorzewska, A;deLange, T
通讯作者：
deLange, T
影响因子：
56.9
作者：
FENG, JL;FUNK, WD;VILLEPONTEAU, B
通讯作者：
VILLEPONTEAU, B