Oncogenes induce genotoxic stress by mitotic processing of unusual replication intermediates.
Oncogenes induce genotoxic stress by mitotic processing of unusual replication intermediates.
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DOI：
10.1083/jcb.201212058
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发表时间：
2013-03-18
期刊：
影响因子：
--
通讯作者：
Lopes M
中科院分区：
文献类型：
--
作者：
Neelsen KJ;Zanini IM;Herrador R;Lopes M
MUS81处理不寻常的复制中间体，如反向分叉，有助于癌基因诱导的双链断裂，并依赖于有丝分裂进入。癌基因诱导的DNA复制应激可激活DNA损伤反应（DDR），这是一种重要的抗癌屏障。在这些情况下，DDR失活会促进基因组不稳定和肿瘤进展，但潜在的分子机制尚不清楚。我们发现Cyclin E和Cdc25A的过表达会迅速减缓复制分叉并诱导分叉逆转，这表明拓扑应力增加。令人惊讶的是，这些表型本身既与染色体断裂无关，也与显著的DDR激活无关。相反，癌基因诱导的DNA断裂和DDR激活发生在持续的G2/M阻滞中，或者在检查点缺陷的情况下，发生在过早的CDK1激活中。MUS81（一种细胞周期调节的核酸酶）的缺失显著限制了染色体断裂，并导致了反向分叉的进一步积累。我们提出，不寻常的复制中间体的核溶解加工介导了癌基因诱导的遗传毒性，并且将这种加工限制在有丝分裂是DNA损伤检查点的核心抗肿瘤功能。
Processing of unusual replication intermediates such as reversed forks by MUS81 contributes to oncogene-induced double-strand breaks and depends on mitotic entry. Oncogene-induced DNA replication stress activates the DNA damage response (DDR), a crucial anticancer barrier. DDR inactivation in these conditions promotes genome instability and tumor progression, but the underlying molecular mechanisms are elusive. We found that overexpression of both Cyclin E and Cdc25A rapidly slowed down replication forks and induced fork reversal, suggestive of increased topological stress. Surprisingly, these phenotypes, per se, are neither associated with chromosomal breakage nor with significant DDR activation. Oncogene-induced DNA breakage and DDR activation instead occurred upon persistent G2/M arrest or, in a checkpoint-defective context, upon premature CDK1 activation. Depletion of MUS81, a cell cycle–regulated nuclease, markedly limited chromosomal breakage and led to further accumulation of reversed forks. We propose that nucleolytic processing of unusual replication intermediates mediates oncogene-induced genotoxicity and that limiting such processing to mitosis is a central anti-tumorigenic function of the DNA damage checkpoints.
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DOI：
10.1083/jcb.200905059
发表时间：
2010-03-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Beck H;Nähse V;Larsen MS;Groth P;Clancy T;Lees M;Jørgensen M;Helleday T;Syljuåsen RG;Sørensen CS
通讯作者：
Sørensen CS
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：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
通讯作者：
Gorgoulis, Vassilis G.
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：
16.8
作者：
Hanada, Katsuhiro;Budzowska, Magda;Kanaar, Roland
通讯作者：
Kanaar, Roland