Impediment of Replication Forks by Long Non-coding RNA Provokes Chromosomal Rearrangements by Error-Prone Restart.
Impediment of Replication Forks by Long Non-coding RNA Provokes Chromosomal Rearrangements by Error-Prone Restart.
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DOI：
10.1016/j.celrep.2017.10.103
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发表时间：
2017-11-21
期刊：
影响因子：
8.8
通讯作者：
Tanaka H
中科院分区：
文献类型：
--
作者：
Watanabe T;Marotta M;Suzuki R;Diede SJ;Tapscott SJ;Niida A;Chen X;Mouakkad L;Kondratova A;Giuliano AE;Orsulic S;Tanaka H
自然停滞的复制叉子被认为是导致肿瘤细胞染色体结构异常的原因。然而，潜在的机制仍然是投机性的，因为捕获自然失速的叉子一直是一个挑战。在这里，我们捕获了肿瘤细胞中自然停滞的分叉，并描绘了环形小染色体(双微小染色体，DM)结构进化的潜在分子过程。复制叉在DM上因与长非编码RNA的转录机器同向碰撞而停滞不前。Rpa、brca2和dna聚合酶eta(Polη)被招募到失速的叉子上。POLη的招募对复制的继续至关重要，因为POLη被敲除导致DM丢失。被挽救的停滞不前的叉子容易出错，并反复切换复制模板，以创建多个短基因组片段的复杂融合。在小鼠身上，这种复杂的融合使MYC周围的基因组区域循环，在肿瘤形成过程中产生DM。我们的结果定义了一条分子路径，将停滞的复制叉子引导到复杂的染色体重排。Watanabe等人。监测癌细胞中自然停滞的叉子，并确定叉子停滞和拯救的分子机制。作者发现，dna聚合酶η在抢救失灵的叉子方面发挥了关键作用。挽救的叉子是不稳定的，多次更换复制模板，创造了多个基因组片段的复杂融合。
Naturally stalled replication forks are considered to cause structurally abnormal chromosomes in tumor cells. However, underlying mechanisms remain speculative, as capturing naturally stalled forks has been a challenge. Here, we captured naturally stalled forks in tumor cells and delineated molecular processes underlying the structural evolution of circular mini-chromosomes (double minute chromosomes, DMs). Replication forks stalled on the DM by the co-directional collision with the transcription machinery for long non-coding RNA. RPA, BRCA2, and DNA polymerase eta (Polη), were recruited to the stalled forks. The recruitment of Polη was critical for replication to continue, as Polη knockdown resulted in DM loss. Rescued stalled forks were error-prone and switched replication templates repeatedly to create complex fusions of multiple short genomic segments. In mice, such complex fusions circularized the genomic region surrounding MYC to create a DM during tumorigenesis. Our results define a molecular path that guides stalled replication forks to complex chromosomal rearrangements. Watanabe et al. monitor naturally stalled forks in cancer cells and define molecular mechanisms underlying fork stalling and rescue. The authors find that DNA polymerase η plays a critical role in rescuing stalled forks. Rescued forks were unstable and switched replication templates several times, creating complex fusions of multiple genomic segments.
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影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
影响因子：
64.8
作者：
Di Micco, Raffaella;Fumagalli, Marzia;di Fagagna, Fabrizio d'Adda
通讯作者：
di Fagagna, Fabrizio d'Adda
影响因子：
64.8
作者：
通讯作者：
--
8q24 基因沙漠：非编码转录活性的绿洲。
影响因子：
3.7
作者：
Huppi K;Pitt JJ;Wahlberg BM;Caplen NJ
通讯作者：
Caplen NJ
影响因子：
64.5
作者：
Barlow JH;Faryabi RB;Callén E;Wong N;Malhowski A;Chen HT;Gutierrez-Cruz G;Sun HW;McKinnon P;Wright G;Casellas R;Robbiani DF;Staudt L;Fernandez-Capetillo O;Nussenzweig A
通讯作者：
Nussenzweig A