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快速的 DNA 复制起始许可保护干细胞的多能性。

Rapid DNA replication origin licensing protects stem cell pluripotency.

机构信息

Department of Biochemistry and Biophysics, The University of North Carolina, Chapel Hill, United States.

Human Pluripotent Stem Cell Core Facility, The University of North Carolina, Chapel Hill, United States.

出版信息

Elife. 2017 Nov 17;6:e30473. doi: 10.7554/eLife.30473.

DOI:10.7554/eLife.30473
PMID:29148972
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5720591/
Abstract

Complete and robust human genome duplication requires loading minichromosome maintenance (MCM) helicase complexes at many DNA replication origins, an essential process termed origin licensing. Licensing is restricted to G1 phase of the cell cycle, but G1 length varies widely among cell types. Using quantitative single-cell analyses, we found that pluripotent stem cells with naturally short G1 phases load MCM much faster than their isogenic differentiated counterparts with long G1 phases. During the earliest stages of differentiation toward all lineages, MCM loading slows concurrently with G1 lengthening, revealing developmental control of MCM loading. In contrast, ectopic Cyclin E overproduction uncouples short G1 from fast MCM loading. Rapid licensing in stem cells is caused by accumulation of the MCM loading protein, Cdt1. Prematurely slowing MCM loading in pluripotent cells not only lengthens G1 but also accelerates differentiation. Thus, rapid origin licensing is an intrinsic characteristic of stem cells that contributes to pluripotency maintenance.

摘要

完整而强大的人类基因组复制需要在许多 DNA 复制起点加载微小染色体维持（MCM）解旋酶复合物，这是一个称为起点许可的关键过程。许可仅限于细胞周期的 G1 期，但不同细胞类型的 G1 期长度差异很大。使用定量单细胞分析，我们发现具有自然短 G1 期的多能干细胞比具有长 G1 期的同基因分化细胞更快地加载 MCM。在向所有谱系分化的最早阶段，MCM 加载与 G1 延长同时减慢，揭示了 MCM 加载的发育控制。相比之下，细胞周期蛋白 E 的异位过表达将短 G1 与快速 MCM 加载解耦。干细胞中快速的许可归因于 MCM 加载蛋白 Cdt1 的积累。在多能细胞中过早减缓 MCM 加载不仅会延长 G1 期，还会加速分化。因此，快速的起始许可特性是多能干细胞维持多能性的内在特征。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2ba/5720591/14e65ef49eb9/elife-30473-fig7-figsupp3.jpg
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