Alternative lengthening of telomeres is a self-perpetuating process in ALT-associated PML bodies.
Alternative lengthening of telomeres is a self-perpetuating process in ALT-associated PML bodies.
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DOI：
10.1016/j.molcel.2020.12.030
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发表时间：
2021-03-04
期刊：
影响因子：
16
通讯作者：
Zou L
中科院分区：
文献类型：
--
作者：
Zhang JM;Genois MM;Ouyang J;Lan L;Zou L
端粒的选择性延长 (ALT) 是由断裂诱导复制 (BIR) 介导的，但 BIR 在端粒上的调节方式尚不清楚。在这里，我们证明端粒 BIR 是一个自我延续的过程。通过将 PML-IV 束缚在端粒上，我们在 ALT 相关的 PML 小体 (APB) 中诱导端粒聚集，并在端粒处诱导 POLD3 依赖性 ATR 反应，表明 BIR 会产生复制应激。 APB 中 BLM 解旋酶活性的消除会消除端粒合成，但会导致端粒之间出现多个染色体桥，揭示了 BLM 在处理端粒间 BIR 中间体中的功能。有趣的是，BLM 在 APB 中的积累需要其自身的解旋酶活性和 POLD3，这表明 BIR 触发前馈循环以进一步招募 BLM。增强 BIR 会诱导 PIAS4 介导的 TRF2 SUMOylation，而 PIAS4 缺失会剥夺 APB 的修复蛋白并损害 ALT 端粒合成。因此，BLM 驱动和 PIAS4 介导的前馈环路在 APB 中运行以维持 BIR，从而提供延长 ALT 端粒的关键机制。端粒 (ALT) 的替代性延长是通过 ALT 相关 PML 小体 (APB) 中的断裂诱导复制 (BIR) 发生的。张等人。表明 BLM 通过解析 APB 中的 BIR 中间体来促进 ALT。此外，BIR 在 APB 中产生复制压力，驱动 SUMO 介导的前馈循环，进一步招募 BIR 蛋白并使 ALT 永久存在。
Alternative lengthening of telomeres (ALT) is mediated by break-induced replication (BIR), but how BIR is regulated at telomeres is poorly understood. Here, we show that telomeric BIR is a self-perpetuating process. By tethering PML-IV to telomeres, we induced telomere clustering in ALT-associated PML bodies (APBs) and a POLD3-dependent ATR response at telomeres, showing that BIR generates replication stress. Ablation of BLM helicase activity in APBs abolishes telomere synthesis but causes multiple chromosome bridges between telomeres, revealing a function of BLM in processing inter-telomere BIR intermediates. Interestingly, the accumulation of BLM in APBs requires its own helicase activity and POLD3, suggesting that BIR triggers a feedforward loop to further recruit BLM. Enhancing BIR induces PIAS4-mediated TRF2 SUMOylation, and PIAS4 loss deprives APBs of repair proteins and compromises ALT telomere synthesis. Thus, a BLM-driven and PIAS4-mediated feedforward loop operates in APBs to perpetuate BIR, providing a critical mechanism to extend ALT telomeres. Alternative lengthening of telomere (ALT) occurs through break-induced replication (BIR) in ALT-associated PML bodies (APBs). Zhang et al. show that BLM promotes ALT by resolving BIR intermediates in APBs. Furthermore, BIR generates replication stress in APBs, driving a SUMO-mediated feedforward loop to further recruit BIR proteins and perpetuate ALT.
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影响因子：
8.8
作者：
Garcia-Exposito L;Bournique E;Bergoglio V;Bose A;Barroso-Gonzalez J;Zhang S;Roncaioli JL;Lee M;Wallace CT;Watkins SC;Opresko PL;Hoffmann JS;O'Sullivan RJ
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通讯作者：
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作者：
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影响因子：
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作者：
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通讯作者：
Reddel RR
DOI：
10.1126/science.1257216
发表时间：
2015-01-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Flynn RL;Cox KE;Jeitany M;Wakimoto H;Bryll AR;Ganem NJ;Bersani F;Pineda JR;Suvà ML;Benes CH;Haber DA;Boussin FD;Zou L
通讯作者：
Zou L