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首页> 外文期刊>Molecular and Cellular Biology >A Mammalian Bromodomain Protein, Brd4, Interacts with Replication Factor C and Inhibits Progression to S Phase
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A Mammalian Bromodomain Protein, Brd4, Interacts with Replication Factor C and Inhibits Progression to S Phase

机译：哺乳动物Bromodomain蛋白，Brd4，与复制因子C相互作用并抑制进展为S期

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Brd4 belongs to the BET family of nuclear proteins that carry two bromodomains implicated in the interaction with chromatin. Expression of Brd4 correlates with cell growth and is induced during early G1 upon mitogenic stimuli. In the present study, we investigated the role of Brd4 in cell growth regulation. We found that ectopic expression of Brd4 in NIH 3T3 and HeLa cells inhibits cell cycle progression from G1 to S. Coimmunoprecipitation experiments showed that endogenous and transfected Brd4 interacts with replication factor C (RFC), the conserved five-subunit complex essential for DNA replication. In vitro analysis showed that Brd4 binds directly to the largest subunit, RFC-140, thereby interacting with the entire RFC. In line with the inhibitory activity seen in vivo, recombinant Brd4 inhibited RFC-dependent DNA elongation reactions in vitro. Analysis of Brd4 deletion mutants indicated that both the interaction with RFC-140 and the inhibition of entry into S phase are dependent on the second bromodomain of Brd4. Lastly, supporting the functional importance of this interaction, it was found that cotransfection with RFC-140 reduced the growth-inhibitory effect of Brd4. Taken as a whole, the present study suggests that Brd4 regulates cell cycle progression in part by interacting with RFC.
机译：Brd4属于核蛋白的BET家族，该家族携带两个与染色质相互作用相关的溴结构域。 Brd4的表达与细胞生长相关，并在有丝分裂刺激的早期G 1 期间被诱导。在本研究中，我们调查了Brd4在细胞生长调节中的作用。我们发现，Brd4在NIH 3T3和HeLa细胞中的异位表达抑制了细胞周期从G 1 到S的过程。免疫共沉淀实验表明，内源性和转染的Brd4与复制因子C（RFC）相互作用，保守的5个-亚基复合物是DNA复制所必需的。体外分析表明，Brd4直接与最大的亚基RFC-140结合，从而与整个RFC相互作用。与体内观察到的抑制活性一致，重组Brd4在体外抑制RFC依赖性DNA延长反应。对Brd4缺失突变体的分析表明，与RFC-140的相互作用和对进入S期的抑制均依赖于Brd4的第二个溴结构域。最后，支持这种相互作用的功能重要性，发现与RFC-140共转染可降低Brd4的生长抑制作用。总的来说，本研究表明Brd4部分通过与RFC相互作用来调节细胞周期进程。

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