Quantitative genetics of phenotypic effects of Matrine and Doxorubicin on yeast

Doxorubicin has been used as a highly effective chemotherapy for decades but with serious side effects, such as cardiotoxicity. Matrine has been reported to have combined anti-cancer effects with cisplatin. The idea of this project is that use yeast to explore the potential combined effects of Doxorubicin and Matrine for reducing the toxicity or improving the effects, and variation in genes responding to the treatment.

Four parent strains and a 4-way Advanced Intercross Line population which from the four parent strains were used as testing strains. The phenotypic results of parent strains indicated that 4 millimolar (mM) Matrine has no significant inhibition to yeast growth on its own. When the drug is combined with 100 micromolar (μM) Doxorubicin, the growth inhibition caused by Doxorubicin is enhanced. Moreover, the treated yeast cells have significant longer budding time than the control and rarely abnormal budding morphology is found in WE and WA. The cell viability is significantly decreased in the Doxorubicin alone and the combined treatment in the WA strain. QTL mapping using a 4-way AIL population was applied and hundreds of QTL intervals were identified. The functions of candidate genes were verified their function via genome deletion collection strains. One of the candidate genes, VRL1, were selected and further validated by Reciprocal Hemizygosity. The further function exploration of its upper part, YML003W, reveals that this gene is involving mutagenesis. The epistasis analysis reveals YML003W is epistatic to some DNA damage repair pathways, including RAD18 and REV3, but not RAD5, suggesting a potential interaction.

Overall, the results suggest a possible synergistic effect of Matrine and Doxorubicin. A novel gene YML003W is identified involving mutagenesis.