The ATR-mediated S phase checkpoint prevents rereplication in mammalian cells when licensing control is disrupted.
The ATR-mediated S phase checkpoint prevents rereplication in mammalian cells when licensing control is disrupted.
复制标题
DOI：
10.1083/jcb.200704138
复制
发表时间：
2007-11-19
期刊：
影响因子：
--
通讯作者：
Wu X
中科院分区：
文献类型：
--
作者：
Liu E;Lee AY;Chiba T;Olson E;Sun P;Wu X
真核细胞中的DNA复制受到许可机制的严格控制，确保每个起点在每个细胞周期中激发一次且仅激发一次。我们证明共济失调毛细血管扩张和Rad3相关（ATR）介导的S期检查点作为一种监督机制，以防止再复制。因此，当ATR检查点完整时，许可控制的破坏将不会诱导哺乳动物细胞中的显著再复制。我们还证明，单链DNA（ssDNA）是初始信号，激活检查点时，在哺乳动物细胞中的许可控制受到损害。我们证明了Cdt1过表达时由微小染色体维持蛋白引起的不受控制的DNA解旋是导致ssDNA积累和检查点激活的重要机制。此外，我们发现复制蛋白A2和视网膜母细胞瘤蛋白都是ATR的下游靶点，对抑制DNA再复制很重要。我们揭示了ATR介导的S期检查点途径阻止DNA再复制的分子机制，从而显着提高了我们对哺乳动物细胞中如何阻止再复制的理解。
DNA replication in eukaryotic cells is tightly controlled by a licensing mechanism, ensuring that each origin fires once and only once per cell cycle. We demonstrate that the ataxia telangiectasia and Rad3 related (ATR)–mediated S phase checkpoint acts as a surveillance mechanism to prevent rereplication. Thus, disruption of licensing control will not induce significant rereplication in mammalian cells when the ATR checkpoint is intact. We also demonstrate that single-stranded DNA (ssDNA) is the initial signal that activates the checkpoint when licensing control is compromised in mammalian cells. We demonstrate that uncontrolled DNA unwinding by minichromosome maintenance proteins upon Cdt1 overexpression is an important mechanism that leads to ssDNA accumulation and checkpoint activation. Furthermore, we show that replication protein A 2 and retinoblastoma protein are both downstream targets for ATR that are important for the inhibition of DNA rereplication. We reveal the molecular mechanisms by which the ATR-mediated S phase checkpoint pathway prevents DNA rereplication and thus significantly improve our understanding of how rereplication is prevented in mammalian cells.
登录
查看更多内容
影响因子：
64.5
作者：
Casper, AM;Nghiem, P;Glover, TW
通讯作者：
Glover, TW
影响因子：
11.4
作者：
Ballabeni, A;Melixetian, M;Helin, K
通讯作者：
Helin, K
DOI：
10.1038/nrm1663
发表时间：
2005-06
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.3
作者：
Green, BM;Li, JJ
通讯作者：
Li, JJ
DOI：
10.1073/pnas.212519499
发表时间：
2002-10-29
影响因子：
11.1
作者：
Broceño, C;Wilkie, S;Mittnacht, S
通讯作者：
Mittnacht, S