Analysis of the role of the Nek family members in adjusting the response to DNA damage in mitochondria

• Grant number: 18/25614-5
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: March 01, 2019
• End date: April 30, 2023
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Jörg Kobarg
• Grantee: Fernando Riback Silva
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 17/03489-1 - From functional studies to searching for new inhibitors for cancer: exploring kinases that regulate the cell cycle of the human NEK family, AP.TEM

Abstract

The members of the Nek kinases (NIMA related kinases) family, were identified as important regulators of cell cycle checkpoints, especially in the G2 transition to M. Although it is one of the families of less studied kinases, recent studies have shown that they may have critical roles in mitosis, separation of centrioles and signaling pathways for DNA damage. These characteristics coupled with the fact that several family members are overexpressed in Cancer or have high mutation rates make them interesting candidates for diagnosis and Cancer therapy. Data from the literature on NEK1 and recently published group studies on NEK5 and NEK4, and new data on NEK10, suggest important roles for NEKs in mitochondrial functions. NEK1 localizes in the mitochondria and the mitochondrial protein VDAC1 is phosphorylated by it. In addition, the expression of a catalytically inactive mutant of NEK1 causes cell death, as well as the expression of a variant S193A of VDAC in Hela cells. These cells also showed an increase in mitochondrial membrane permeability. In contrast, overexpression of the VDAC S193E phosphomimetic variant in wild-type Hela cells protects cells from apoptosis. Thus the project aims to analyze the role of these members of the NEK family in the regulation of the response to DNA damage in mitochondria. (AU)