Molecular mechanisms underlying maintenance of genome stability

Cells in our body are challenged every day by DNA damage arising as a result of both endogenous and exogenous insults. The ability of cells to repair DNA lesions is essential for correct propagation of genetic information. The most cytotoxic DNA lesion is DNA double-strand break (DSB) while oxidative DNA damage is one of the most frequent lesions. The aim of this thesis was to improve current the knowledge of the molecular mechanisms underlying the repair of DSBs and oxidative DNA damage. The major source of oxidative damage in cells are reactive oxygen species that are constantly generated as by-products of cell metabolism. One of the most frequent lesions is 7,8- dihydro-8-oxo-guanine (8-oxo-G) that gives rise to 8-oxo-G:A mispairs during DNA replication and if left unrepaired, results in accumulation of DNA mutations. We found that Werner helicase (WRN) physically interacts with DNA polymerase λ (Polλ) and stimulates DNA gap-filling by Polλ opposite to 8-oxo-G followed by strand displacement synthesis in MutY DNA glycosylase homolog (MUTYH) initiated base excision repair (BER) of 8-oxo-G:A mispairs. There are two major pathways involved in repair of DSBs: homologous recombination (HR) and non-homologous end joining (NHEJ). NHEJ is highly error-prone while HR is error-free. There are two..