To cope with DNA damages induced by endogenous and exogenous agents, cells employ both DNA repair and DNA damage tolerance (DDT) mechanisms. Translesion synthesis (TLS) is an important DDT... Show moreTo cope with DNA damages induced by endogenous and exogenous agents, cells employ both DNA repair and DNA damage tolerance (DDT) mechanisms. Translesion synthesis (TLS) is an important DDT mechanism in mammalian cells. Mammalian TLS is performed by at least five key proteins. These TLS DNA polymerases play roles in bypassing unrepaired DNA adducts during and after S-phase, thereby allowing completion of genome duplication. However, since TLS is a mutagenic process, its mechanism must be tightly controlled. Thus far, the in vivo role of each TLS polymerase in response to DNA damages in mammalian cells and organisms has largely remained unclear. Furthermore, the relative contribution of each TLS polymerase is also poorly understood. In this thesis, I have used cell lines with single or combined deficiencies in TLS polymerases to explore the absolute and relative in vivo contributions of these TLS-polymerases in resp onse to DNA damages induced by food-derived genotoxins and UV light. Furthermore, I have studied the genomic and cellular consequences of unreplicated DNA lesions, resulting from defects in TLS. Using TLS-defective mice, I have addressed the importance of TLS in preventing organismal premature aging. Show less
Temviriyanukul, P.; Hees-Stuivenberg, S. van; Delbos, F.; Jacobs, H.; Wind, N. de; Jansen, J.G. 2012
