pH-induced variations in the TK1 gene model

Publication date: Available online 28 November 2019Source: Mutation Research/Genetic Toxicology and Environmental MutagenesisAuthor(s): Julien Massonneau, Chloë Lacombe-Burgoyne, Guylain BoissonneaultAbstractA physiological decrease in extracellular pH (pHe) alters the efficiency of DNA repair and increases formation of DNA double-strand breaks (DSBs). Whether this could translate into genetic instability and variations, was investigated using the TK6 cell model, in which positive selection of the TK1 gene loss-of-function mutations can be achieved from resistance to trifluorothymidine. Cell exposure to suboptimal pH (down to 6.9) for 3 weeks resulted in the 100% frequency of a stronger frameshift mutation that has spread to both TK1 alleles, whereas weaker frameshift mutations within the 3’exon were eliminated during the selection. Suboptimal pHe values were also found to alter the proportion of the TK1 splicing variant expressed as percent spliced in index values and promote selection of truncated exons as well as intron retention. Although recovery at pH 7.4 did not reverse the selected frameshift mutation, reversal of splice variants and exon truncation towards control values were observed. Hence, suboptimal pHe can induce a combination of mutational events and splicing alterations within the same gene in the resistant clones. This model of positive selection for loss-of-function clearly demonstrates that suboptimal pHe may confer a similar growth advantage whe...
Source: Mutation Research Genetic Toxicology and Environmental Mutagenesis - Category: Genetics & Stem Cells Source Type: research

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Source: International Journal of Surgery Case Reports - Category: Surgery Source Type: research
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Source: Student Doctor Network - Category: Universities & Medical Training Authors: Tags: What Are My Chances? WAMC Medical Source Type: forums
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Source: The Annals of Thoracic Surgery - Category: Cardiovascular & Thoracic Surgery Source Type: research
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Source: Yakugaku Zasshi : Journal of the Pharmaceutical Society of Japan - Category: Drugs & Pharmacology Authors: Tags: Yakugaku Zasshi Source Type: research
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Source: South African Journal of Surgery - Category: Surgery Tags: S Afr J Surg Source Type: research
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Source: Annali Italiani di Chirurgia - Category: Surgery Tags: Ann Ital Chir Source Type: research
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