Michael Lisby – University of Copenhagen

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Michael Lisby

Cell biology of DNA repair

In response to DNA damage, the DNA repair machinery is assembled at the site of damage in a highly choreographed manner depending on the chromosomal context, the type of damage, cell cycle phase and other factors.

We study the spatiotemporal organisation of DNA repair processes in the cell nucleus with special focus on homologous recombination (Symington et al. 2014), which plays a key role in the repair of DNA double-strand breaks, restart of stalled or collapsed replication forks, and telomere length homeostasis in telomerase negative cells (Silva et al. 2016). To identify the fundamental biological mechanisms underlying DNA repair, we combine genome-wide cell biological and genetic analyses in the yeast Saccharomyces cerevisiae with more focused studies in vertebrate cell lines (Gallina et al. 2015). In addition to studying the proteins that catalyse DNA repair, we also aim to identify and understand the post-translational modifications that regulate these processes such as sumoylation, phosphorylation, acetylation and ubiquitylation.

If chromosome aberrations are not repaired in a timely manner prior to cell division, they may lead to DNA anaphase bridges in mitosis (see illustration below), chromosome breakage, and ultimately missegregation of genetic material (Germann et al. 2014; Pedersen et al. 2015). DNA anaphase bridges have been linked to chromosomal fragile sites (see the Hickson Lab website), which are chromosome regions prone to exhibit gaps and breaks on metaphase chromosomes, especially when cells are challenged by DNA replication stress. Notably, more than 50% of recurrent cancer mutations have been linked to fragile sites. Our aim is to identify the proteins and mechanisms responsible for sensing and resolving DNA anaphase bridges in a manner that preserves chromosome integrity and to understand the coordination of these processes with mitosis.

pictures of anaphase bridges

Caption: Dpb11-coated anaphase bridges activate the NoCut checkpoint to delay cytokinesis (Germann et al, 2014).

Lisby Lab website: https://www1.bio.ku.dk/english/research/fg/transkription/ 


Gallina, I., C. Colding, P. Henriksen, P. Beli, K. Nakamura et al., 2015 Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control. Nat Commun 6: 6533.

Germann, S. M., V. Schramke, R. T. Pedersen, I. Gallina, N. Eckert-Boulet et al., 2014 TopBP1/Dpb11 binds DNA anaphase bridges to prevent genome instability. J Cell Biol 204: 45-59.

Pedersen, R. T., T. Kruse, J. Nilsson, V. H. Oestergaard and M. Lisby, 2015 TopBP1 is required at mitosis to reduce transmission of DNA damage to G1 daughter cells. J Cell Biol 210: 565-582.

Silva, S., V. Altmannova, S. Luke-Glaser, P. Henriksen, I. Gallina et al., 2016 Mte1 interacts with Mph1 and promotes crossover recombination and telomere maintenance. Genes Dev 30: 700-717.

Symington, L. S., R. Rothstein and M. Lisby, 2014 Mechanisms and regulation of mitotic recombination in Saccharomyces cerevisiae. Genetics 198: 795-835.