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The human protein kinase NEK1: the characterization of its physiological activation by DNA damage and its use as a biological marker and potential therapeutic target in Thyroid Cancer

Grant number: 18/13775-4
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): August 01, 2018
Effective date (End): July 31, 2022
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Jörg Kobarg
Grantee:Luidy Kazuo Issayama
Home 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 NIMA related kinases (NEK) family were identified as important cell cycle checkpoint regulators, especially at G2 to M transition. Despite been one of the less studied kinase families, recent data showed that they might have crucial role in mitosis, centriole separation and signaling pathway for DNA damage. Those features together with the fact that several members of the family are overexpressed on Cancer or exhibit high mutation rates makes them interesting targets for diagnosis and Cancer therapy. NEK1 has pleiotropic functions and mutations of its gene have been reported in Cancer and ciliopathies, such as Polycystic Kidney Disease (PKD), besides some genetic diseases such as Mohr Syndrome, Amyotrophic Lateral Sclerosis (ALS) and Short-Rib Thoracic Dysplasia (SRTD). Previous studies from our group resulted in the identification of 11 proteins that interacts with NEK1. A screening of human fetal brain cDNA library using the regulatory domain of hNEK1 kinase resulted in the identification of proteins involved in the etiology of PKD, such as KIF3A, tuberin e alpha-catulin, confirming the major role of NEK1 and its interactors at the development of the disease. We also identified proteins involved in repair mechanisms of DNA damage (ATRX, MRE11, p53 BP1). Further studies have shown the role of NEK1 on DNA repair, mainly in repair pathway by homologous recombination. It was observed that after induction of DNA damage there is an increase on expression and activity of NEK1. It migrates from cytoplasm to nucleus, to the regions where the damage occured. Additionally, cells which didn't expressed NEK1 presented high hypersensibility to lethal effects of ionizing radiation. Recent data published by our group, in addition to reporting the structure of the kinase domain from NEK1, we showed from proteomic and phosphoproteomic data that after treatment of cells with the chemotherapeutic cisplatin, NEK1 interacts with proteins from other repair pathways, such as proteins from Fanconi pathway (FANCA) and from Mismatch repair (MSH6), among others. Together, those data suggest that NEK1 activates several DNA repair pathways, mainly to solve bulky damages involving DNA crosslinks (cisplatin). Additionally, the maor role of NEK1 makes it an interesting target for Cancer inhibition, along with chemotherapy and radiotherapy (chemosensitization approach). The chemotherapy treatment together with anti-NEK1 inhibitors - which would inhibit the activation of multiple DNA repair pathways -, would leave Cancer cells more vulnerable to DNA damage compared to normal cells. (AU)