DNA double-strand breaks (DSBs) are the most hazardous type of DNA damage threatening genomic stability. In response to this challenge, eukaryotes have evolved conserved mechanisms for DNA damage response and repair pathways. Although these pathways are highly conserved, they are not fully understood. Maintaining a balance between error-prone mechanisms, such as Non-Homologous End-Joining (NHEJ), and high-fidelity mechanisms, such as Homologous Recombination (HR), is crucial for cell fitness. This balance is particularly exerted at the level of licensing HR through the initial step of the pathway known as DNA end resection. Therefore, a comprehensive study of this step is essential for understanding genetic diseases, such as cancer, and holds significant potential for guiding future therapeutic strategies.
Cohesin complexes, with their tripartite ring-like structure, are highly conserved factors known for their roles in preventing genome instability. The cohesin complex consists of three subunits, and the kleisin subunit varies between mitotic and meiotic phases—Rad21/Scc1 during mitosis and Rec8 during meiosis. It has been described roles for cohesin in chromosome segregation and DNA repair, but as short, all based in providing close proximity of sister chromatids. But little it’s known about an active function in DNA repair further tethering DNA molecules, e. g. participating in the decision of NHEJ/HR pathway or mediating early DNA resection. Unraveling how cohesin regulates various aspects of DNA metabolism is not only a crucial biological question but also holds clear relevance for human health.
This project aimed to challenge and expand the preconceived notions of mitotic and meiotic cohesin complexes, particularly exploring the potential roles of the REC-8 kleisin outside of meiosis. Additionally, it sought to illuminate cohesin-specific functions of different complexes and compare the active contributions of SCC-1- and REC-8-cohesin complexes in various aspects of DNA metabolism, including DNA resection and repair. Using Caenorhabditis elegans as a model system provided a unique opportunity to study systemic DNA damage response mechanisms in a tissue-specific manner, focusing on mitotically proliferating undifferentiated germ cells and embryonic development. The project successfully achieved all its objectives, both scientifically and from a career point of view.
