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pH-induced variations in the TK1 gene model.

Julien Massonneau¹, Chloë Lacombe-Burgoyne¹, Guylain Boissonneault¹

¹Dept of Biochemistry and Functional Genomics, Faculty of Medicine & Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.

Mutation Research. Genetic Toxicology and Environmental Mutagenesis

|February 24, 2020

Summary

Suboptimal extracellular pH (pHe) induces genetic instability by causing mutations and altering gene splicing. This pH-induced instability may provide a growth advantage for cells, particularly within tumor suppressor genes.

Keywords:

DNA repair Double-strand breaks Genetic instability Mutagenesis pH

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Area of Science:

Molecular Biology
Genetics
Cancer Research

Background:

Physiological decreases in extracellular pH (pHe) are known to affect DNA repair efficiency and increase DNA double-strand breaks (DSBs).
The potential link between altered pHe, genetic instability, and cellular variations remains an area of investigation.

Purpose of the Study:

To investigate whether suboptimal extracellular pH can induce genetic instability and variations.
To examine the impact of prolonged exposure to suboptimal pHe on gene mutations and splicing within a cellular model.

Main Methods:

Utilized the TK6 cell model for positive selection of TK1 gene loss-of-function mutations.
Exposed cells to suboptimal pH (down to 6.9) for three weeks.
Analyzed mutations, splicing variants, and exon alterations in the TK1 gene.

Main Results:

Suboptimal pHe exposure led to a 100% frequency of a stronger frameshift mutation in both TK1 alleles, eliminating weaker mutations.
Altered proportions of TK1 splicing variants, promoted selection of truncated exons, and intron retention.
Recovery at pH 7.4 partially reversed splicing alterations and exon truncation but not the selected frameshift mutation.

Conclusions:

Suboptimal extracellular pH can induce a combination of mutational events and splicing alterations within the same gene.
This pH-induced genetic instability may confer a growth advantage, especially when occurring in tumor suppressor genes.