Genome-wide effects of DNA replication on nucleotide excision repair of UV-Induced DNA lesions
Azgari, Cem (2020) Genome-wide effects of DNA replication on nucleotide excision repair of UV-Induced DNA lesions. [Thesis]
Replication can cause unrepaired DNA damages to lead mutations that might result in cancer. Nucleotide excision repair is the primary repair mechanism that prevents melanoma cancers by removing UV-induced bulky DNA adducts. However, the role of replication on nucleotide excision repair, in general, is yet to be clarified. Recently developed methods Damage-seq and XR-seq map damage formation and nucleotide excision repair events respectively, in various conditions. Here, we applied Damageseq and XR-seq methods to UV-irradiated HeLa cells synchronized at two stages of the cell cycle: early S phase, and late S phase. We analyzed the damage and repair events along with replication origins and replication domains of HeLa cells. We found out that in both early and late S phase cells, early replication domains are more efficiently repaired relative to late replication domains. The results also revealed that repair efficiency favors the leading strands around replication origins. Moreover, we observed that the repair efficiency of the strands around replication origins is inversely correlated with the number of melanoma mutations. In summary, our findings suggest that nucleotide excision repair have a role in replication-associated mutational strand asymmetry of cancer genome, which was previously unknown.
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