Study of repair of chemotherapy-induced DNA damage using Saccharomyces cerevisiae as a model system

Project leader: Miroslav Chovanec
Project duration: 2015 - 2018

Many anticancer regimes manifest toxicity against cancer cells via induction of DNA damage. Even though this toxicity cannot be targeted exclusively to cancer cells yet, nevertheless chemotherapy or radiotherapy kills cancer cells more efficiently than normal cells. To better understand mechanism(s) of action of anticancer therapy as well as to improve its efficiency, deeper knowledge on DNA damage response and repair processes is essential. Upon DNA damage induction, an attempt to repair DNA damage is one of the main downstream events. Not surprisingly, DNA damage detection, signaling and repair mechanisms interfere with efficiency of anticancer therapy. Here, we plan to use the budding yeast Saccharomyces cerevisiae to better understand molecular mechanisms of repair of those DNA lesions that are considered to be the most severe in clinical oncology. We intend to further characterize S phase specific arm of interstrand cross-link repair in yeast that has recently been discovered in our laboratory. This repair pathway shares significant similarity with, and is likely evolutionary counterpart of, DNA damage response and repair pathway that is defective in patients suffering from Fanconi anemia. In addition, this project is aimed at uncovering further details of newly discovered regulatory mechanism that is involved in DNA double-strand break repair pathway choice and that is based on physical interaction between the key components of homologous recombination and non-homologous end-joining (NHEJ). Also, the role SUMOylation of components of the DNA ligase IV complex in this regulation as well as in regulation of NHEJ process by itself will be examined. Finally, we wish to delineate a role of proteins that are called alkyltrasferase-like proteins because they share homology with O6-alkylguanine DNA alkyltransferase, a protein that is involved in removal of alkylation damage from DNA and that plays a crucial role in resistance of tumor cells against therapy inducing such DNA damage types. Our main focus here is to reveal a possibility of cross-talk between them and other DNA repair pathways dealing with alkylated DNA, particularly nucleotide excision repair and mismatch repair pathways.

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