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BBB seminar: Geir Slupphaug

Regulation of uracil-DNA repair by post-translational modification of UNG2


Geir Slupphaug
Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim

Post-translational modifications (PTMs) appear to be functional modulators of many DNA repair proteins. We are presently mapping PTMs and their potential biological implications in base excision repair (BER) of uracil. During the cell cycle, the nuclear uracil-DNA glycosylase UNG2 is stepwise phosphorylated at three Cdc kinase consensus sites. Phospho-mimicking mutants and in-vitro phosphorylation studies indicate that the specific phosphorylation pattern modulates the catalytic activity of UNG2 and interactions with replicating chromatin. In late S/G2 phase distinct phosphorylations apparently form a phosphodegron in the UNG2 N-terminus, thereby promoting ubiquitinylation, detachment from replication protein A (RPA), and degradation. The phosphodegron is homologous to that of CyclinE, C-Myc and c-Jun which all are recognized by the ubiquitin E3-kinase Fbw7. Although Fbw7 may also ubiquitinylate UNG2, it is apparently not required, and UNG2 is efficiently ubiquitinylated by the E2 ligase UBCH2 in vitro . Interestingly, a UV-inducible phosphorylation at T6 promotes detachment from proliferating cell nuclear antigen (PCNA), while the association to RPA is retained. Thus, the distinct phosphorylation patterns of UNG2 observed through the cell cycle and after genotoxic stress are likely to regulate the enzymatic activity and lifetime of UNG2, and direct the enzyme to distinct functional repair complexes in the chromatin.

Host: Marit Bakke <marit.bakke@biomed.uib.no>, Department of Biomedicine