Helle Ulrich

Function of ubiquitin and SUMO in DNA damage bypass

Tolerance to replication-blocking lesions is essential for viability in the presence of genotoxic agents. Although clearly beneficial in terms of cell survival, damage tolerance mechanisms are not always entirely desirable in higher organisms, because lesion bypass is often an error-prone process that is recognized as the major cause of DNA damage-induced mutations. For eukaryotic cells it is therefore of crucial importance to keep damage tolerance mechanisms under tight control and prevent their unrestrained activity in situations where they are not needed. Research in our lab is focused on the system responsible for regulating the activity of damage tolerance, the RAD6 pathway. Key components of this group of genes encode enzymes of the ubiquitin¹ and SUMO conjugation machinery, systems of protein modification involved in the regulation of various cellular functions. The target protein in the context of damage bypass is the processivity clamp of replicative DNA polymerases, PCNA². Monoubiquitination and SUMO modification activate damage-tolerant polymerases for mutagenic translesion synthesis^{3 and 4}, while multiubiquitination induces an alternative, error-free damage avoidance pathway.

We expect that our research will provide mechanistic insight into damage-induced mutagenesis pathways and hope that an analysis of the contributions of ubiquitin and SUMO to this process would facilitate the development of strategies for active intervention, for example in the context of cancer therapy, where suppression of damage-tolerance is of particular importance for effective treatment.

Projects available to incoming postdoctoral fellows will focus either on the signaling pathways that induce the individual PCNA modifications, including cell cycle- and checkpoint-specific aspects, or on the events that are elicited by PCNA mono- and multiubiquitination. Alternatively, an analysis of SUMO substrates in the context of DNA damage tolerance is possible. Although we use primarily yeast as a model system, extension of the work to a vertebrate system is possible and desirable. The work will involve methods in cell and molecular biology as well as biochemical approaches and classical yeast genetics. The lab welcomes applicants who have a strong background in either protein biochemistry or yeast genetics.

References

1. Ulrich HD and Jentsch S. EMBO J 2000; 19: 3388-3397.
2. Hoege C, et al. Nature 2002; 419: 135-141.
3. Stelter P and Ulrich HD. Nature 2003; 425: 188-191.
4. Ulrich HD. Cell Cycle 2004; 3: 15-18.