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Assessing the role of S6K1 and S6K2 in DNA damage response and repair

Grant number: 23/02842-0
Support Opportunities:Scholarships abroad - Research Internship - Doctorate (Direct)
Effective date (Start): July 17, 2023
Effective date (End): January 16, 2024
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Fernando Moreira Simabuco
Grantee:Mariana Marcela Góis
Supervisor: Sylvie M. Noordermeer
Host Institution: Faculdade de Ciências Aplicadas (FCA). Universidade Estadual de Campinas (UNICAMP). Limeira , SP, Brazil
Research place: Leiden University Medical Center (LUMC) , Netherlands  
Associated to the scholarship:20/08684-0 - Study of the interaction between PARP1 and S6K2 and its relation with Cancer metabolism and DNA repair, BP.DD


Genomic instability is a hallmark of cancer characterized by an increased rate of alterations in the genome, which favors tumorigenesis and tumor progression. Luckily, cells have mechanisms such as DNA repair, which respond to the presence of DNA damage and help maintain genomic integrity and stability. Recently, the S6K1 protein, a target of mTORC1, has been linked to DNA repair. Particularly, its role in mismatch repair and homologous recombination (HR) has been described. The mTORC1 pathway is a metabolic pathway that responds to the availability of mitogens such as insulin and amino acids, and its activation leads to cell growth and proliferation signaling, mediated by phosphorylation of its targets S6K1 and S6K2. Although S6K1 and S6K2 may have distinct cellular functions, S6K2 has been described as the "neglected S6K", since in general studies analyze only S6K1. Indeed, there are no data demonstrating the role of S6K2 in DNA damage repair (DDR). Considering that S6K2 but not S6K1 interacts with PARP1 and other DDR proteins, as previously described by our group, our objective is to describe the role of S6K2 in DDR, especially PARP1 and BRCA1/2-dependent pathways, which are important to breast cancer. To clarify this, we will use molecular biology techniques such as siRNAs, CRISPR-Cas9 to generate S6Ks knockout in breast cancer cell models and DNA repair reporter cell lines. We will also use chemical tools such as PARP1 and S6Ks inhibitors, and analyze the effect of S6Ks knockout on the effectiveness of different chemotherapies. (AU)

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