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

• Grant number: 20/08684-0
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: January 01, 2021
• End date: December 31, 2025
• Field of knowledge: Health Sciences - Nutrition - Nutrition Biochemistry
• Principal Investigator: Fernando Moreira Simabuco
• Grantee: Mariana Marcela Góis
• Host Institution: Faculdade de Ciências Aplicadas (FCA). Universidade Estadual de Campinas (UNICAMP). Limeira , SP, Brazil
• Associated research grant: 18/14818-9 - Study of molecular targets important for the control of cancer metabolism: the mTOR/S6K pathway as a central role, AP.JP2
• Associated scholarship(s): 23/02842-0 - Assessing the role of S6K1 and S6K2 in DNA damage response and repair, BE.EP.DD

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)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MANCINI, MARIANA C. S.; MORELLI, ANA P.; SEVERINO, MATHEUS B.; PAVAN, ISADORA C. B.; ZAMBALDE, ERIKA P.; GOIS, MARIANA M.; DA SILVA, LUIZ G. S.; QUINTERO-RUIZ, NATHALIA; ROMEIRO, CAIO F.; DOS SANTOS JR, DANIEL F. G.; et al. Knockout of NRF2 triggers prostate cancer cells death through ROS modulation and sensitizes to cisplatin. Journal of Cellular Biochemistry, v. 123, n. 12, p. 14-pg., 2022-10-03. (20/09310-6, 20/09133-7, 16/06457-0, 20/13660-2, 20/09527-5, 15/00311-1, 20/08684-0, 18/14818-9, 19/00607-9, 19/25582-9, 19/25731-4)