Richards Logan, Das Souradip, Nordman Jared T
Department of Biological Sciences, Vanderbilt University, Nashville, TN 37203, USA.
Genes (Basel). 2022 Mar 20;13(3):550. doi: 10.3390/genes13030550.
Successful duplication of the genome requires the accurate replication of billions of base pairs of DNA within a relatively short time frame. Failure to accurately replicate the genome results in genomic instability and a host of diseases. To faithfully and rapidly replicate the genome, DNA replication must be tightly regulated and coordinated with many other nuclear processes. These regulations, however, must also be flexible as replication kinetics can change through development and differentiation. Exactly how DNA replication is regulated and how this regulation changes through development is an active field of research. One aspect of genome duplication where much remains to be discovered is replication timing (RT), which dictates when each segment of the genome is replicated during S phase. All organisms display some level of RT, yet the precise mechanisms that govern RT remain are not fully understood. The study of Rif1, a protein that actively regulates RT from yeast to humans, provides a key to unlock the underlying molecular mechanisms controlling RT. The paradigm for Rif1 function is to delay helicase activation within certain regions of the genome, causing these regions to replicate late in S phase. Many questions, however, remain about the intricacies of Rif1 function. Here, we review the current models for the activity of Rif1 with the goal of trying to understand how Rif1 functions to establish the RT program.
基因组的成功复制需要在相对较短的时间内精确复制数十亿个碱基对的DNA。未能精确复制基因组会导致基因组不稳定和一系列疾病。为了忠实地快速复制基因组，DNA复制必须受到严格调控，并与许多其他核过程协调。然而，这些调控也必须具有灵活性，因为复制动力学可随发育和分化而变化。DNA复制究竟是如何调控的，以及这种调控如何随发育而变化，是一个活跃的研究领域。基因组复制中仍有许多有待发现的方面是复制时间（RT），它决定了基因组的每个片段在S期何时被复制。所有生物都表现出一定程度的RT，但控制RT的精确机制仍未完全了解。对Rif1（一种从酵母到人类都能积极调节RT的蛋白质）的研究为揭示控制RT的潜在分子机制提供了关键。Rif1功能的范例是延迟基因组某些区域内解旋酶的激活，导致这些区域在S期后期复制。然而，关于Rif1功能的复杂性仍有许多问题。在这里，我们回顾了目前关于Rif1活性的模型，旨在试图了解Rif1如何发挥作用来建立RT程序。
