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DNA damage occurs spontaneously during replication due to various processes that cause replication fork blockage. Single stranded DNA gaps are major lesions that accumulate during replication. DNA damage tolerance (DDT) pathways ensure fork restart and filling of DNA gaps and are crucial for genome integrity. One main DDT pathway, template switching, involves recombination and uses the undamaged information of the sister duplex to bypass DNA lesions mostly in an error-free manner, but the mechanism involved remains elusive.
Ongoing research projects
We plan to uncover the mechanism of template switching by identifying the genetic pathways/factors involved in the formation and processing of template switch intermediates, the regulation of these events by various DNA damage response pathways, as well as their coordination with ongoing replication, chromatin structure and cell-cycle transitions. Second, we aim to identify the structure of DDT intermediates and their precursors using various techniques. Previous work in the lab revealed that SUMOylation is not only promoting the formation and resolution of template switch intermediates, but that it also affects the choice of the recombination pathway involved in template switching (Branzei et al, Cell, 2006; Branzei et al, Nature, 2008). The differences between these two recombination pathways, which lead to the formation of similar chromatin structures involving sister chromatid junctions, as well as their link to chromatin structure and chromosome integrity remains unknown, and represents another topic of ongoing research in the lab. Thirdly, we are interested in identifying how SUMOylation is activated by replication stress and the mechanism by which it promotes replication and adequate DNA damage response.