Construction and validation of a yeast model system for studying in vivo the susceptibility to nucleoside analogues of DNA polymerase gamma allelic variants

Mitochondrial dysfunctions have been observed in subjects treated with antiretroviral nucleoside analogues, such as stavudine, as they can interfere with the activity of DNA polymerase gamma. Recently, stavudine-induced mitochondrial toxicity was associated to POLG mutations R964C and E1143G. A yeast model system useful to evaluate the association between D4T toxicity and mutations in MIP1, the yeast ortholog of POLG, was constructed and validated as a tool for pharmacogenetics research. We showed that mutant Mip1pR964C and possibly Mip1pE1143G are more sensitive to stavudine, and that stavudine has the potential to cause mitochondrial toxicity in heterozygous subjects harboring recessive mutations.