Telomere Length Determines TERRA and R-Loop Regulation through the Cell Cycle
Telomere Length Determines TERRA and R-Loop Regulation through the Cell Cycle
复制标题
DOI：
10.1016/j.cell.2017.06.006
复制
发表时间：
2017-06-29
期刊：
影响因子：
64.5
通讯作者：
Luke, Brian
中科院分区：
文献类型：
--
作者：
Graf, Marco;Bonetti, Diego;Luke, Brian
维持最小的端粒长度对于防止细胞衰老是必不可少的。当在没有端粒酶的情况下出现非常短的端粒时，它们可以通过同源定向修复（HDR）进行修复，以防止过早衰老。目前还不清楚为什么最短的端粒是HDR的目标。我们证明，非编码RNA TERRA积累的HDR促进RNA-DNA杂交（R环）优先在非常短的端粒。TERRA和R环水平的增加（仅在短端粒处）分别是由于Rat 1和RNase H2核酸酶的RNA降解局部缺陷造成的。因此，TERRA降解与端粒复制的协调在缩短的端粒处改变。短端粒的R环持久性有助于DNA损伤反应（DDR）的激活，并促进Rad 51重组酶的募集。因此，TERRA和TERRA R环的端粒长度依赖性调节是复制性衰老速率的关键决定因素。
Maintenance of a minimal telomere length is essential to prevent cellular senescence. When critically short telomeres arise in the absence of telomerase, they can be repaired by homology-directed repair (HDR) to prevent premature senescence onset. It is unclear why specifically the shortest telomeres are targeted for HDR. We demonstrate that the non-coding RNA TERRA accumulates as HDR-promoting RNA-DNA hybrids (R-loops) preferentially at very short telomeres. The increased level of TERRA and R-loops, exclusively at short telomeres, is due to a local defect in RNA degradation by the Rat1 and RNase H2 nucleases, respectively. Consequently, the coordination of TERRA degradation with telomere replication is altered at shortened telomeres. R-loop persistence at short telomeres contributes to activation of the DNA damage response (DDR) and promotes recruitment of the Rad51 recombinase. Thus, the telomere length-dependent regulation of TERRA and TERRA R-loops is a critical determinant of the rate of replicative senescence.