Stabilization of Reversed Replication Forks by Telomerase Drives Telomere Catastrophe.
Stabilization of Reversed Replication Forks by Telomerase Drives Telomere Catastrophe.
复制标题
通过端粒酶稳定相反的复制叉驱动端粒灾难。
DOI：
10.1016/j.cell.2017.11.047
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发表时间：
2018-01-25
期刊：
影响因子：
64.5
通讯作者：
Boulton SJ
中科院分区：
文献类型：
--
作者：
Margalef P;Kotsantis P;Borel V;Bellelli R;Panier S;Boulton SJ
端粒的维持主要取决于端粒酶和RTEL 1的不同活性，端粒酶添加端粒重复序列以解决末端复制问题，RTEL 1破坏端粒处的DNA二级结构以促进复制体进展。在这里，我们确定了逆转复制叉是端粒酶的病理底物，也是Rtel 1 −/−细胞中端粒灾难的来源。抑制端粒酶向端粒的募集，但不抑制其活性，或通过PARP 1抑制或消耗UBC 13或ZRANB 3来阻断复制叉逆转，可以防止功能失调的端粒在RTEL 1缺陷细胞中的快速积累。在这种情况下，我们建立了端粒酶结合逆转复制叉抑制端粒复制，这可以通过防止复制叉通过耗尽RECQ 1或PARG重新启动模仿。我们的研究结果使我们提出端粒酶不适当地结合到端粒内，并抑制逆转复制叉的重新启动，这会损害复制并导致端粒非常短。阻断端粒酶募集挽救了Rtel 1 −/−细胞中的端粒灾难端粒内的逆转复制叉被端粒酶异常结合阻断复制叉逆转挽救了端粒酶诱导的端粒灾难端粒酶阻止逆转复制叉在端粒处的重新启动。
Telomere maintenance critically depends on the distinct activities of telomerase, which adds telomeric repeats to solve the end replication problem, and RTEL1, which dismantles DNA secondary structures at telomeres to facilitate replisome progression. Here, we establish that reversed replication forks are a pathological substrate for telomerase and the source of telomere catastrophe in Rtel1−/− cells. Inhibiting telomerase recruitment to telomeres, but not its activity, or blocking replication fork reversal through PARP1 inhibition or depleting UBC13 or ZRANB3 prevents the rapid accumulation of dysfunctional telomeres in RTEL1-deficient cells. In this context, we establish that telomerase binding to reversed replication forks inhibits telomere replication, which can be mimicked by preventing replication fork restart through depletion of RECQ1 or PARG. Our results lead us to propose that telomerase inappropriately binds to and inhibits restart of reversed replication forks within telomeres, which compromises replication and leads to critically short telomeres. Blocking telomerase recruitment rescues telomere catastrophe in Rtel1−/− cells Reversed replication forks within telomeres are aberrantly bound by telomerase Blocking fork reversal rescues telomere catastrophe induced by telomerase Telomerase prevents restart of reversed replication forks at telomeres Telomerase can, paradoxically, contribute to telomere shortening by stabilizing stalled replication forks at chromosome ends.
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影响因子：
4.5
作者：
Ballew BJ;Joseph V;De S;Sarek G;Vannier JB;Stracker T;Schrader KA;Small TN;O'Reilly R;Manschreck C;Harlan Fleischut MM;Zhang L;Sullivan J;Stratton K;Yeager M;Jacobs K;Giri N;Alter BP;Boland J;Burdett L;Offit K;Boulton SJ;Savage SA;Petrini JH
通讯作者：
Petrini JH
影响因子：
11.4
作者：
Betous, Remy;Pillaire, Marie-Jeanne;Pierini, Laura;van der Laan, Siem;Recolin, Benedicte;Ohl-Seguy, Emma;Guo, Caixia;Niimi, Naoko;Gruz, Petr;Nohmi, Takehiko;Friedberg, Errol;Cazaux, Christophe;Maiorano, Domenico;Hoffmann, Jean-Sebastien
通讯作者：
Hoffmann, Jean-Sebastien
影响因子：
3.5
作者：
Gelot C;Magdalou I;Lopez BS
通讯作者：
Lopez BS
DOI：
10.1083/jcb.201410061
发表时间：
2015-07-20
期刊：
The Journal of cell biology
影响因子：
--
作者：
Drosopoulos WC;Kosiyatrakul ST;Schildkraut CL
通讯作者：
Schildkraut CL
影响因子：
20.3
作者：
Gramatges, Maria M.;Qi, Xiaodong;Bertuch, Alison A.
通讯作者：
Bertuch, Alison A.