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Moldovan, George-Lucian (2006): Regulation of replication-linked functions by PCNA and SUMO. Dissertation, LMU München: Faculty of Biology
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Abstract

Genomic integrity largely depends on the accurate replication and faithful transmission of the genetic information to the progeny each time a cell divides. To ensure the fidelity of these fundamental processes, highly sophisticated protein networks have evolved. This study investigated how the diverse mechanisms for maintaining genomic integrity are integrated and coordinated at the replication fork. In the first part, the roles of post-translational modifications with ubiquitin and SUMO in regulating replication through DNA lesions were investigated. Previous work in S. cerevisiae showed that post-translational modifications of the replication factor PCNA control DNA repair activities of the replisome. PCNA is a homotrimeric ring-shaped protein that encircles DNA and confers processivity to DNA polymerases during DNA synthesis. Moreover, being devoid of enzymatic activity, PCNA is perfectly suited to act as a platform for recruitment of factors to the replication fork, including DNA repair enzymes, chromatin remodelers and replication regulators. PCNA modifications by ubiquitin govern two distinct modes of lesion bypass, either channeling the repair processes into error-prone translesion synthesis by recruiting specialized polymerases, or promoting an error-free mechanism involving a template switch to the sister chromatid. In addition, PCNA-modification by SUMO inhibits the third major bypass mechanism, namely recombinational repair, by recruiting the anti-recombinogenic helicase Srs2. In this study, the importance and universality of PCNA-modifications could be demonstrated by showing that PCNA ubiquitylation in human and chicken cells is well conserved. Interestingly, SUMO modification appeared less preserved, indicating that the pathways controlled by PCNA modifications are used to different degrees throughout species. A further finding of this thesis was the identification of DNA polymerase