Correcting Nucleotide Excision Repair-associated diseases

Maintenance of genome integrity via repair of DNA damage is a key biological process required to suppress diseases, many of which have little/no specific treatment options. Recently the concept of targeting one pathway to rescue another defective pathway has emerged as an approach to ameliorate pathologies that occur in rare diseases. In this proposal we aim to develop approaches to alleviate rare diseases resulting from defects in the DNA repair pathway, termed nucleotide excision repair (NER). Thus, we have generated cell lines with mutations in genes associated with defective NER. Next, we will use genetic and drug/compound high throughput screening approaches to systematically identify the combinatorial loss of the second genearget that results in rescue. We will confirm our findings with patient cells. Finally, we shall shed light on the mechanism by which the genetic or compound/drug rescue is functioning, hence this project may lead to the discovery of new treatments for these debilitating diseases.

Maintenance of genome integrity via repair of DNA damage is a key biological process required to suppress diseases, many of which have little/no specific treatment options. Recently the concept of targeting one pathway to rescue another defective pathway has emerged as an approach to ameliorate pathologies that occur in rare diseases. In this project we have developed approaches to alleviate rare diseases resulting from defects in the DNA repair pathways termed nucleotide excision repair (NER) and Fanconi anemia (FA). Thus, we have generated cell lines with mutations in genes associated with these diseases. Next, we used genetic and drug high throughput screening approaches to systematically identify the combinatorial loss of the second gene/target that results in rescue. Having confirmed that we can alleviate hallmarks in patient derived cells we next investigated the cellular processes involved. In summary, in this project we identified drug and genetic approaches to alleviate symptoms of rare diseases associated with DNA repair defects.