How pH deregulation favors the hallmarks of cancer

Koltai, Tomas; Fliegel, Larry; Baltazar, Fátima; Reshkin, Stephan J.; Alfarouk, Khalid O.; Cardone, Rosa Angela; Afonso, José António

doi:10.1016/b978-0-443-15461-4.00008-4

Cited by 1 publication

(1 citation statement)

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“…Finally, the phenomenon described herein may signify genetic assimilation as a widespread adaptive mechanism for challenging complex environments. An emerging hallmark of cancer involves perturbations in pHi that manifest similarly to rho R109H/Δ ydcI cells, where the pHi is maintained higher than that of the extracellular environment 96,97 . These alterations can be induced through arginine to histidine mutations that confer pH-sensing capabilities, particularly in global regulators, subsequently altering gene expression and reshaping the cellular environment 36,37 .…”

Section: Discussionmentioning

confidence: 99%

Evolution of pH-sensitive transcription termination during adaptation to repeated long-term starvation

Worthan,

McCarthy,

Delaleau

et al. 2024

Preprint

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Fluctuating environments that consist of regular cycles of co-occurring stress are a common challenge faced by cellular populations. For a population to thrive in constantly changing conditions, an ability to coordinate a rapid cellular response is essential. Here, we identify a mutation conferring an arginine-to-histidine (Arg to His) substitution in the transcription terminator Rho. TherhoR109H mutation frequently arose inE. colipopulations experimentally evolved under repeated long-term starvation conditions, during which feast and famine result in drastic environmental pH fluctuations. Metagenomic sequencing revealed that populations containing the rho mutation also possess putative loss-of-function mutations inydcI, which encodes a recently characterized transcription factor associated with pH homeostasis. Genetic reconstructions of these mutations show that therhoallele confers a plastic alkaline-induced reduction of Rho function that, when found in tandem with aΔydcIallele, leads to intracellular alkalinization and genetic assimilation of Rho mutant function. We further identify Arg to His substitutions at analogous sites inrhoalleles from species originating from fluctuating alkaline environments. Our results suggest that Arg to His substitutions in global regulators of gene expression can serve to rapidly coordinate complex responses through pH sensing and shed light on how cellular populations across the tree of life use environmental cues to coordinate rapid responses to complex, fluctuating environments.

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