Interstitial telomere sequences disrupt break-induced replication and drive formation of ectopic telomeres.
Interstitial telomere sequences disrupt break-induced replication and drive formation of ectopic telomeres.
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DOI：
10.1093/nar/gkaa1081
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发表时间：
2020-12-16
影响因子：
14.9
通讯作者：
Symington LS
中科院分区：
文献类型：
--
作者：
Stivison EA;Young KJ;Symington LS
断裂诱导复制（BIR）是一种用于修复单端DNA双链断裂的机制，例如在折叠的复制叉或侵蚀的端粒处形成的断裂。BIR不是利用典型的复制叉，而是由迁移的D环驱动，并与高频率的诱变相关。在这里，我们表明，当BIR遇到间质端粒序列（ITS），机械频繁终止，导致异位端粒的形成。将ITS转化为功能性端粒的主要机制是通过端粒聚合酶催化的端粒重复序列的加成，并以同源性定向修复作为后备机制。BIR的终止和异位端粒的产生由Mph 1/FANCM解旋酶促进，该解旋酶具有分解D环的能力。具有播种新端粒的潜力但缺乏天然端粒序列的独特特征的其它序列在野生型细胞中不以显著的频率终止BIR。然而，这些序列可以形成异位端粒，如果BIR是不那么进行性。我们的研究结果支持了一个模型，其中ITS本身的功能，如倾向于形成二级结构和端粒蛋白结合，构成了挑战BIR和增加的D-环解旋酶解离的脆弱性，从而促进异位端粒的形成。
Break-induced replication (BIR) is a mechanism used to heal one-ended DNA double-strand breaks, such as those formed at collapsed replication forks or eroded telomeres. Instead of utilizing a canonical replication fork, BIR is driven by a migrating D-loop and is associated with a high frequency of mutagenesis. Here we show that when BIR encounters an interstitial telomere sequence (ITS), the machinery frequently terminates, resulting in the formation of an ectopic telomere. The primary mechanism to convert the ITS to a functional telomere is by telomerase-catalyzed addition of telomeric repeats with homology-directed repair serving as a back-up mechanism. Termination of BIR and creation of an ectopic telomere is promoted by Mph1/FANCM helicase, which has the capacity to disassemble D-loops. Other sequences that have the potential to seed new telomeres but lack the unique features of a natural telomere sequence, do not terminate BIR at a significant frequency in wild-type cells. However, these sequences can form ectopic telomeres if BIR is made less processive. Our results support a model in which features of the ITS itself, such as the propensity to form secondary structures and telomeric protein binding, pose a challenge to BIR and increase the vulnerability of the D-loop to dissociation by helicases, thereby promoting ectopic telomere formation.
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影响因子：
16
作者：
Fasching, Clare L.;Cejka, Petr;Kowalczykowski, Stephen C.;Heyer, Wolf-Dietrich
通讯作者：
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影响因子：
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通讯作者：
Aharoni A