Study of the interaction between PARP1 and S6K2 and its relation with Cancer metabolism and DNA repair

Abstract

PARP-1 is a protein involved in DNA repair, DNA replication, transcription, genome organization and apoptosis. Once activated by DNA damage, PARP proteins are able to post-translation- modify proteins in a process called parylation, using NAD+ as substrate. Several studies have proved the feasibility of the use of PARP inhibitors as adjuvant chemotherapeutic agents for the treatment of Cancer or as a monotherapy against tumor cells that are defective in DNA repair mechanisms, like in BRCA-deficient Cancer cells. In an article published by our group we have shown that PARP-1 efficiently co-immunoprecipitates with S6K2 and other studies have also demonstrated correlation between PARP-1 and the mTOR/S6Ks pathway. Here we aim to further explore the relationship between PARP-1 and S6Ks, since we still don't know if S6Ks regulate or are regulated by PARP1. By performing immunoprecipitation experiments we intend to characterize the interaction between PARP-1 and S6K2. Besides, we will evaluate whether PARP-1 is able to parylate S6Ks or S6Ks are able to phosphorylate PARP-1 and how this alters the functions of the proteins. Finally, the relationship between PARP-1 and mTOR/S6Ks will be explored in the Cancer context, using a Breast Cancer model and inhibitors of PARP-1. This project may contribute for the understanding on how Cancer cells regulate metabolism in the presence of DNA damage or how nutrient availability connects to DNA repair machinery. (AU)