A deoxynucleoside triphosphate triphosphohydrolase promotes cell cycle progression inCaulobacter crescentus

Abstract

AbstractIntracellular 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 bacteriumCaulobacter crescentustermedflagellar signaling suppressor C(fssC) to clarify the role of Dgts in cell cycle regulation. DeletingfssCincreases dNTP levels and extends the G1 phase of the cell cycle. We determined that the segregation and duplication of the origin of replication (oriC) is delayed in ΔfssC, but the rate of replication elongation is unchanged. We conclude that dNTP hydrolysis by FssC promotes the initiation of DNA replication through a novel nucleotide signaling pathway. 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 both prokaryotic and eukaryotic 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 describe a nucleotide signaling pathway that regulates when cells will begin DNA replication. We show that this pathway promotes the transition from the G1 to the S phase of the cell cycle in the bacteriumCaulobacter crescentusand propose that this pathway is prevalent in all domains of life.