Bypass of an epigenetic S-phase transcriptional module by convergent nutrient stress signals

The signals feeding into bacterial S-phase transcription are poorly understood. Cellular cycling in the alpha-proteobacterium is driven by a complex circuit of at least three transcriptional modules that direct sequential promoter firing during the G1, early and late S cell cycle phases. In alpha-proteobacteria, the transcriptional regulator GcrA and the CcrM methyltransferase epigenetically activate promoters of cell division and polarity genes that fire in S-phase. By evolving cells to cycle and differentiate in the absence of the GcrA/CcrM module, we discovered that phosphate deprivation and (p)ppGpp alarmone stress signals converge on S-phase transcriptional activation. The cell cycle oscillations of the CtrA protein, the transcriptional regulator that implements G1 and late S-phase transcription, are essential in our evolved mutants, but not in wild-type cells, showing that the periodicity in CtrA abundance alone can sustain cellular cycling without GcrA/CcrM. While similar nutritional sensing occurs in other alpha-proteobacteria, GcrA and CcrM are not encoded in the reduced genomes of obligate intracellular relatives. We thus propose that the nutritional stress response induced during intracellular growth obviated the need for an S-phase transcriptional regulator.