Proteomic Profiling Reveals a Specific Role for Translesion DNA Polymerase η in the Alternative Lengthening of Telomeres.
Proteomic Profiling Reveals a Specific Role for Translesion DNA Polymerase η in the Alternative Lengthening of Telomeres.
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DOI：
10.1016/j.celrep.2016.10.048
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发表时间：
2016-11-08
期刊：
影响因子：
8.8
通讯作者：
O'Sullivan RJ
中科院分区：
文献类型：
--
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
癌细胞依赖于端粒酶的激活或端粒(ALT)途径的替代延长来维持端粒和存活。ALT涉及同源重组(HR)依赖的交换和/或HR相关的端粒DNA合成。利用邻近依赖的生物素化(BioID)，我们试图确定使用这些不同的端粒延长机制的癌细胞中的端粒蛋白质组。我们的分析显示，多个DNA修复网络汇聚在ALT端粒。其中包括专门的跨病变DNA合成(TLS)蛋白FANCJ-RAD18-PCNA，以及最值得注意的DNA聚合酶ETa(POLη)。我们观察到，在有丝分裂过程中，POLη的缺失导致ALT活性的增加和依赖于POLδ的端粒δ的合成。我们认为POLη在控制ALT端粒复制应激、维持端粒重组在可耐受水平以及通过POLδ刺激DNA合成方面发挥重要作用。
Cancer cells rely on the activation of telomerase or the alternative lengthening of telomeres (ALT) pathways for telomere maintenance and survival. ALT involves homologous recombination (HR)-dependent exchange and/or HR-associated synthesis of telomeric DNA. Utilizing proximity-dependent biotinylation (BioID), we sought to determine the proteome of telomeres in cancer cells that employ these distinct telomere elongation mechanisms. Our analysis reveals that multiple DNA repair networks converge at ALT telomeres. These include the specialized translesion DNA synthesis (TLS) proteins FANCJ-RAD18-PCNA and, most notably, DNA polymerase eta (Polη). We observe that the depletion of Polη leads to increased ALT activity and late DNA polymerase δ (Polδ)-dependent synthesis of telomeric DNA in mitosis. We propose that Polη fulfills an important role in managing replicative stress at ALT telomeres, maintaining telomere recombination at tolerable levels and stimulating DNA synthesis by Polδ.