Research projects

Cells promote DNA damage repair and maintain genome integrity through a complex signaling network called DNA Damage Response (DDR), in which the post-translational modifications of involved proteins are crucial. Former advances by the Biointeractomics group allowed us to identify an ample set of DDR-related proteins—at both the cell nucleus and cytoplasm—interacting with respiratory cytochrome c (Cc). Cc functioning is finely regulated by post-translational modifications, mainly phosphorylation of tyrosine residues among others. Our findings with phosphomimetic Cc mutants at tyrosines 48 and 87 revealed significant structural and dynamic changes that strongly alter the hemeprotein functionality and the interactions with its targets. In this project, we proposed a model for the role of extramitochondrial Cc going beyond apoptosis signaling in the cytoplasm. Indeed, Cc migration to the nucleus soon after DNA damage—even before caspase cascade activation and apoptosome formation in the cytoplasm—allows the interaction of the hemeprotein with a variety of well-known histone chaperones, namely ANP32A/B, NPM and SET-TAF-Ib, involved in chromatin remodeling and DNA damage response. Our research findings do show that nuclear Cc impairs dephosphorylation events and triggers p53 activation during the repair of injured DNA. Such findings are highly relevant and have been published in high-impact journals such as Nature Communications (Gomila et al., 2022), Nature Structural & Molecular Biology (González-Arzola et al., 2022), and Computational and Structural Biotechnology Journal (Casado-Combreras et al., 2022). The project’s main aim is to elucidate how cells respond to DNA damage and further contribute to our understanding of the molecular basis for cancer and neurodegenerative diseases. The current project will indeed allow us to determine whether phosphorylation of Cc at specific residues could be used as a biomarker in human diseases, thereby opening the door to potential therapeutic applications and design of new drugs.