Hellenbrand Chandler N, Stevenson David M, Gromek Katarzyna A, Amador-Noguez Daniel, Hershey David M
Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
J Bacteriol. 2025 Jun 24;207(6):e0014525. doi: 10.1128/jb.00145-25. Epub 2025 Jun 2.
Intracellular pools of deoxynucleoside triphosphates (dNTPs) are strictly maintained throughout the cell cycle to ensure accurate and efficient DNA replication. DNA synthesis requires an abundance of dNTPs, but elevated dNTP concentrations in nonreplicating cells delay entry into S phase. Enzymes known as deoxyguanosine triphosphate triphosphohydrolases (Dgts) hydrolyze dNTPs into deoxynucleosides and triphosphates, and we propose that Dgts restrict dNTP concentrations to promote the G1 to S phase transition. We characterized a Dgt from the bacterium termed () to clarify the role of Dgts in cell cycle regulation. Deleting increases dNTP levels and extends the G1 phase of the cell cycle through a mechanism independent of the response regulator CtrA. Segregation and duplication of the chromosomal origin of replication () are delayed in ∆, but the rate of replication elongation is unchanged. We conclude that dNTP hydrolysis by FssC promotes the initiation of DNA replication. This work further establishes Dgts as important regulators of the G1 to S phase transition, and the high conservation of Dgts across all domains of life implies that Dgt-dependent cell cycle control may be widespread in many organisms.IMPORTANCECells must faithfully replicate their genetic material in order to proliferate. Studying the regulatory pathways that determine when a cell initiates DNA replication is important for understanding fundamental biological processes, and it can also improve the strategies used to treat diseases that affect the cell cycle. Here, we identify a nucleotide signaling pathway that influences when cells begin DNA replication. We show that this pathway promotes the transition from the G1 to the S phase of the cell cycle in the bacterium and propose that this pathway is prevalent in all domains of life.
脱氧核苷三磷酸（dNTP）的细胞内池在整个细胞周期中都受到严格维持，以确保准确而高效的DNA复制。DNA合成需要大量的dNTP，但在非复制细胞中dNTP浓度升高会延迟进入S期。被称为脱氧鸟苷三磷酸三磷酸水解酶（Dgts）的酶将dNTP水解为脱氧核苷和三磷酸，我们提出Dgts会限制dNTP浓度以促进G1期到S期的转变。我们对来自名为（）的细菌中的一种Dgt进行了表征，以阐明Dgts在细胞周期调控中的作用。删除会增加dNTP水平，并通过一种独立于应答调节因子CtrA的机制延长细胞周期的G1期。在∆中，染色体复制起点（）的分离和复制会延迟，但复制延伸速率不变。我们得出结论，FssC介导的dNTP水解促进了DNA复制的起始。这项工作进一步确立了Dgts作为G1期到S期转变的重要调节因子，并且Dgts在生命所有域中的高度保守性意味着依赖Dgt的细胞周期控制可能在许多生物体中广泛存在。重要性细胞必须忠实地复制其遗传物质才能增殖。研究决定细胞何时启动DNA复制的调控途径对于理解基本生物学过程很重要，并且还可以改进用于治疗影响细胞周期的疾病的策略。在这里，我们确定了一条影响细胞何时开始DNA复制的核苷酸信号通路。我们表明，该通路促进了细菌中从细胞周期的G1期到S期的转变，并提出该通路在生命的所有域中都很普遍。
