Laboratory of Genomic Stability, Institute of Molecular Biology, Bulgarian Academy of Sciences, Acad. G., Bonchev Str. Bl.21, 1113 Sofia, Bulgaria.
Molecules. 2021 Dec 24;27(1):97. doi: 10.3390/molecules27010097.
Cells have evolved elaborate mechanisms to regulate DNA replication machinery and cell cycles in response to DNA damage and replication stress in order to prevent genomic instability and cancer. The E3 ubiquitin ligase SCF in is involved in the DNA replication and DNA damage stress response, but its effect on cell growth is still unclear. Here, we demonstrate that the absence of Dia2 prolongs the cell cycle by extending both S- and G2/M-phases while, at the same time, activating the S-phase checkpoint. In these conditions, Ctf4-an essential DNA replication protein and substrate of Dia2-prolongs its binding to the chromatin during the extended S- and G2/M-phases. Notably, the prolonged cell cycle when Dia2 is absent is accompanied by a marked increase in cell size. We found that while both DNA replication inhibition and an absence of Dia2 exerts effects on cell cycle duration and cell size, Dia2 deficiency leads to a much more profound increase in cell size and a substantially lesser effect on cell cycle duration compared to DNA replication inhibition. Our results suggest that the increased cell size in ∆ involves a complex mechanism in which the prolonged cell cycle is one of the driving forces.
细胞已经进化出复杂的机制来调节 DNA 复制机制和细胞周期，以响应 DNA 损伤和复制应激，从而防止基因组不稳定性和癌症。在 中，E3 泛素连接酶 SCF 参与 DNA 复制和 DNA 损伤应激反应，但它对细胞生长的影响尚不清楚。在这里，我们证明了 Dia2 的缺失通过延长 S 期和 G2/M 期来延长细胞周期，同时激活 S 期检查点。在这些条件下，作为 Dia2 的底物和必需的 DNA 复制蛋白的 Ctf4 在延长的 S 期和 G2/M 期延长其与染色质的结合。值得注意的是，当 Dia2 缺失时，细胞周期延长伴随着细胞大小的显著增加。我们发现，尽管 DNA 复制抑制和 Dia2 的缺失都会对细胞周期持续时间和细胞大小产生影响，但与 DNA 复制抑制相比，Dia2 缺失导致细胞大小显著增加，对细胞周期持续时间的影响要小得多。我们的结果表明，∆ 中的细胞大小增加涉及一种复杂的机制，其中延长的细胞周期是驱动力之一。
