Research Projects
Structural characterization of factors involved in DNA-protein crosslink repair
The project research goal is to elucidate the molecular mechanisms behind the DNA-protein crosslink repair pathway. Our structural studies aim to solve near-atomic details of the SPRTN-dependent DPC repair complex, the SPRTN:p97 complex and a novel DPC factor, ACRC. Obtained knowledge will be fundamentally important for a deeper understanding of the DPCR pathway and thus for the developing research on p97 and SPRTN inhibitors for the purpose of targeted clinical therapies in cancerogenesis and aging. In terms of methodology, our studies will offer novel approaches for investigating DNA repair complexes and disordered protein regions using cryo-EM.
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This project is a bilateral project jointly funded by Slovenian and Croatian Science Foundations (project number IPS-2020-01-4225, 2020-2023). A collaborative project includes two research groups: Marjetka Podobnik’s lab at the National Chemistry Institute in Ljubljana (Slovenia), and Popovic lab at Institute Ruder Boskovic in Zagreb, Croatia.
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Deciphering DNA-Protein Crosslink Repair in vivo using CRISPR/Cas9 genome editing in zebrafish model
To date, most aspects of DPCR are poorly understood including identification of the repair complexes, relationship between different pathways, how is the pathway choice made and the mechanistic link between impaired DPCR and cancer, aging and neurodegenerative diseases. So far, existing approaches have not addressed the orchestration of the DPCR pathways on the organismal level. Therefore, how defective DPC repair translates into disease phenotypes remains largely unknown. Recently, in the group, we have implemented zebrafish mutant and gene knock-out methods using CRISPR/Cas and fluorescent reporter assay for rapid germ line transmission screens and established novel methods to measure DPC repair in vivo using the zebrafish model. This approach represents a first step toward understanding the requirements for distinct repair complexes in different cellular and tissue-specific backgrounds. Using a range of techniques across the fields of molecular and cell biology and in vivo zebrafish model, we aim to unravel the mechanisms of DPC repair and try to understand how DPCs drive processes of aging, cancerogenesis and neurodegeneration.ccc