Ulrich Rass

Mechanisms of DNA repair

A variety of cellular DNA repair mechanisms resolve the many exogenous and endogenous DNA damages that constantly affect the genome. Defects in these DNA repair processes have been linked to genome instability, premature aging syndromes, and heritable cancers.
We combine biochemical approaches, yeast genetics, and cell-based assays to elucidate the identity and function of DNA repair enzymes. Particular attention will be paid to homologous recombination (HR) repair. HR promotes faithful repair of DNA double strand breaks and, crucially, facilitates the recovery of stalled or broken replication forks. Many proteins involved in this pathway have been found mutated in cancers (e.g. BRCA1 and BRCA2), making the tumors susceptible to synthetic lethal approaches of anticancer therapy, such as inhibition of DNA single strand break repair by PARP inhibitors. On the other hand, cancer cells may excessively rely on HR in certain settings. It has been shown that activated oncogenes generate replication stress in precancerous lesions, and since HR can promote repair of broken replication forks, inhibition of HR may provide an opportunity for intervention. Given that HR impacts on cancer at multiple levels, it is important to fully understand the specific roles and interplay of the over 200 proteins estimated to play a part in the many sub-pathways of HR.
Our work will contribute to understanding the fundamental mechanisms of HR and support the development of new strategies for anticancer therapy.

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Ulrich Rass
Gabi Gruber
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