Pena, Jennifer Marie
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CitationPena, Jennifer Marie. 2020. Graduate Student. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractPseudomonas aeruginosa is an opportunistic pathogen of humans that is on the Center for Disease Control’s list of top drug resistant threats in the United States. In this gram-negative bacterium the alp system encodes a programmed cell death (PCD) pathway that is switched on in a subset of cells in response to DNA damage. AlpA is the central regulator of this pathway, but how AlpA positively regulates the alpBCDE cell lysis genes was not known. Here we present evidence that AlpA exerts its regulatory effects by acting as a processive antiterminator rather than a classical transcription activator. In particular, we present evidence that AlpA positively regulates the alp genes, as well as genes in a second newly identified operon, by recognizing specific sites on the promoter DNA then directly binding RNA polymerase (RNAP) and allowing it to bypass intrinsic terminators positioned downstream. We identify two distinct portions of RNAP that AlpA interacts with—the β-flap and region 1.1 of σ70 and show that the activity of AlpA is promoted by the alarmone ppGpp which is produced by the cell in response to stress. Through its response to ppGpp, AlpA allows the integration of environmental cues into the decision to execute a programmed cell death pathway that is linked to the virulence of the organism.
Citable link to this pagehttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37365814
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