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DNA replication is fundamental for life, yet a detailed understanding of bacterial DNA replication is limited outside the organisms  Escherichia coli  and  Bacillus subtilis . Many bacteria, including mycobacteria, encode no identified homologs of helicase loaders or regulators of the initiator protein DnaA, despite these factors being essential for DNA replication in  E .  coli  and  B .  subtilis . In this study we discover that a previously uncharacterized protein, Rv0004, from the human pathogen  Mycobacterium tuberculosis  is essential for bacterial viability and that depletion of  Rv0004  leads to a block in cell cycle progression. Using a combination of genetic and biochemical approaches, we found that Rv0004 has a role in DNA replication, interacts with DNA and the replicative helicase DnaB, and affects DnaB-DnaA complex formation. We also identify a conserved domain in Rv0004 that is predicted to structurally resemble the N-terminal protein-protein interaction domain of DnaA. Mutation of a single conserved tryptophan within Rv0004’s DnaA N-terminal-like domain leads to phenotypes similar to those observed upon  Rv0004  depletion and can affect the association of Rv0004 with DnaB. In addition, using live cell imaging during depletion of  Rv0004 , we have uncovered a previously unappreciated role for DNA replication in coordinating mycobacterial cell division and cell size. Together, our data support that  Rv0004  encodes a homolog of the recently identified DciA family of proteins found in most bacteria that lack the DnaC-DnaI helicase loaders in  E .  coli  and  B .  subtilis . Therefore, the mechanisms of Rv0004 elucidated here likely apply to other DciA homologs and reveal insight into the diversity of bacterial strategies in even the most conserved biological processes.

Rv0004 is a new essential member of the mycobacterial DNA replication machinery