Department of Molecular Biology and Genetics and Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21210, United States.
Semin Immunol. 2010 Dec;22(6):362-9. doi: 10.1016/j.smim.2010.09.001. Epub 2010 Oct 30.
In developing lymphocytes, V(D)J recombination is subject to tight spatial and temporal regulation. An emerging body of evidence indicates that some of these constraints, particularly with respect to locus specificity and cell cycle phase, are enforced by regulatory cues that converge directly on the RAG proteins themselves. Active chromatin is bound by RAG-2 through a specific histone modification that may serve the recombinase as an allosteric activator as well as a docking site. RAG-1 possesses intrinsic histone ubiquitin ligase activity, suggesting that the recombinase not only responds to chromatin modification but is itself able to modify chromatin. The cyclin A/Cdk2 component of the cell cycle clock triggers periodic destruction of RAG-2, thereby restricting V(D)J recombination to the G0/G1 cell cycle phases. These examples illustrate that the RAG proteins, in addition to their direct actions on DNA, are able to detect and respond to intracellular signals, thereby coordinating recombinase activity with intracellular processes such as cell division and transcription.
在淋巴细胞的发育过程中，V(D)J 重组受到严格的时空调控。越来越多的证据表明，其中一些限制因素，特别是在基因座特异性和细胞周期阶段方面，是由直接作用于 RAG 蛋白本身的调节信号所强制执行的。活性染色质通过 RAG-2 结合特定的组蛋白修饰，这种修饰可能作为变构激活剂以及结合位点为重组酶提供服务。RAG-1 具有内在的组蛋白泛素连接酶活性，这表明重组酶不仅能响应染色质修饰，而且自身能够修饰染色质。细胞周期时钟的周期蛋白 A/Cdk2 成分触发 RAG-2 的周期性破坏，从而将 V(D)J 重组限制在 G0/G1 细胞周期阶段。这些例子表明，除了直接作用于 DNA 之外，RAG 蛋白还能够检测和响应细胞内信号，从而将重组酶活性与细胞分裂和转录等细胞内过程协调起来。
