CHAPTER 6: Global Regulation of Transcription by Nucleotides and (p)ppGpp

The activity of the RNA polymerase (RNAP) molecular machine is highly regulated in response to the external environment. In this chapter, we focus on regulation of transcription by ribonucleotides, the substrates of RNAP, and by nucleotide derivatives that act as signaling molecules to control transcription. We explain how the concentration of the ribonucleotides directly regulates RNAP activity during transcription initiation by affecting the rate limiting step of nucleotide addition, which depends on both the identity of the initiating nucleotide and the promoter sequence. We describe recent breakthroughs about how the stress signaling nucleotide alarmones guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp) [collectively known as (p)ppGpp] regulate the synthesis or degradation of the substrates of the transcription machinery regulated transcription in an organism-specific manner, or they directly modify the activity of the core transcription machinery itself in conjunction with the transcription factor DnaK suppressor A (DksA). Finally, we describe emerging work characterizing how (p)ppGpp and DksA act beyond transcription initiation by coordinating transcription with other macromolecular machines involved in DNA replication and repair to promote genome stability.