Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA.
Curr Genet. 2021 Aug;67(4):539-543. doi: 10.1007/s00294-021-01170-7. Epub 2021 Mar 8.
The precise regulation of the entry into S phase is critical for preventing genome instability. The first step in the initiation of eukaryotic DNA synthesis occurs in G1 phase cells and involves the loading of the conserved MCM helicase onto multiple origins of replication in a process known as origin licensing. In proliferating metazoan cells, an origin-licensing checkpoint delays initiation until high levels of MCM loading occur, with excess origins being licensed. One function of this checkpoint is to ensure that S phase can be completed in the face of replication stress by activation of dormant MCM bound origins. However, when both metazoan and yeast cells enter S phase from quiescence or G0 phase, a non-growing but reversible cell cycle state, origins are significantly under-licensed. In metazoan cells, under-licensing is the result of a compromised origin-licensing checkpoint. In budding yeast, our study has revealed that under-licensing can be attributed to the chromatin structure at a class of origins that is inhibitory to the binding of MCM. Thus, defects in multiple pathways may contribute to the failure to fully license origins in quiescent cells re-entering the cell cycle, thereby promoting a higher risk of genome instability.
精确调控 S 期进入对于防止基因组不稳定性至关重要。真核生物 DNA 合成起始的第一步发生在 G1 期细胞中,涉及将保守的 MCM 解旋酶加载到多个复制起始点上,这一过程称为起始许可。在增殖的后生动物细胞中,起始许可检查点延迟起始,直到 MCM 加载达到高水平,多余的起始点被许可。该检查点的一个功能是通过激活休眠的 MCM 结合起始点来确保在复制应激下完成 S 期。然而,当后生动物和酵母细胞从静止或 G0 期进入 S 期时,细胞处于非生长但可逆转的细胞周期状态,起始点的许可显著不足。在后生动物细胞中,许可不足是起始许可检查点受损的结果。在芽殖酵母中,我们的研究表明,许可不足可归因于一类起始点的染色质结构,该结构抑制了 MCM 的结合。因此,多个途径的缺陷可能导致静止细胞重新进入细胞周期时不能完全许可起始点,从而增加基因组不稳定性的风险。