DNA is constantly damaged by endogenous and exogenous sources and it has been shown that 80 to 90% of all human cancers are ultimately due to DNA damage. Organisms thus require efficient DNA repair systems to maintain their genomes in a functional state. Nucleotide excision repair (NER) recognizes structurally highly diverse damages, and it is our goal to obtain a general understanding of the sequential process of this repair pathway and exploit its role in cancer therapy. RecQ helicases assume key functions to maintain genomic integrity and are frequently upregulated in many cancers. We investigate the intricate molecular network of RecQ4 to decipher its function and to assess it as a target for cancer therapy.
Research Highlights 2017/2018
One major player in the NER cascade is the general transcription factor TFIIH.
TFIIH is a multiprotein complex consisting of ten subunits. We solved structures of a complex formed by the p34 N-terminal vWA and p44 C-terminal zinc binding domains. Our data reveal the presence of a redundant interaction network within core-TFIIH, which may serve to minimize the susceptibility to mutational impairment. This analysis provides first insights into why so far no mutations in the p34 or p44 core-TFIIH subunits have been identified that lead to the hallmark nucleotide excision repair syndromes xeroderma pigmentosum or trichothiodystrophy.
RecQ4 is one of five human RecQ helicases that are fundamental for genome maintenance. We solved the structure of the core RecQ4 helicase unit, revealing unique structural domains that are absent in other RecQ proteins. Combined with our functional analysis, we suggest that RecQ4 may employ a helicase mechanism that is different from that of all other human RecQ family members. Our results set the stage to examine the molecular basis of unique RecQ4 genome maintenance functions and analyse the structure-function relationship of patient mutations leading to RecQ4 associated human diseases.
The concepts that we have already and will continue to unveil by tackling basic research questions that elucidate mechanisms of DNA repair and maintaining genomic integrity will guide our approach towards translational aspects of these processes. We will develop pipelines for the development of new inhibitors that target specific steps in the analysed pathways. Our analysis will not only provide insights at the atomic level, but will also lead to their evaluation in appropriate animal models. Consequently, we will follow a more wholistic approach to maximize our knowledge about the important translational implications fostered by our basic research.