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The regulators of M ycobacterium tuberculosis DNA replication are largely unknown. Here, we demonstrate that in synchronously replicating M . tuberculosis, MtrA access to origin of replication ( ori C) is enriched in the post-replication ( D) period. The increased ori C binding results from elevated MtrA phosphorylation ( MtrA∼ P) as evidenced by reduced expression of dna N, dna A and increased expression of select cell division targets. Overproduction of gain-of-function MtrAY102C advanced the MtrA ori C access to the C period, reduced dna A and dna N expression, interfered with replication synchrony and compromised cell division. Overproduction of wild-type ( MtrA+) or phosphorylation-defective MtrAD56N did not promote ori C access in the C period, nor affected cell cycle progression. MtrA interacts with DnaA signaling a possibility that DnaA helps load MtrA on ori C. Therefore, ori C sequestration by MtrA∼ P in the D period may normally serve to prevent untimely initiations and that DnaA- MtrA interactions may facilitate regulated ori C replication. Finally, despite the near sequence identity of MtrA in M . smegmatis and M . tuberculosis, the M . smegmatis ori C is not MtrA-target. We conclude that M . tuberculosis ori C has evolved to be regulated by MtrA and that cell cycle progression in this organisms are governed, at least in part, by oscillations in the MtrA∼ P levels. [ABSTRACT FROM AUTHOR]