Interplay between post-translational modification systems in Archaea

Post-translational modifications (PTMs) play critical roles in cell biology, drug development, and synthetic biology strategies aimed at advancing human health. While our understanding of PTM diversity continues to grow, deciphering their impact on protein structure, function, and downstream biological processes remains challenging. This project builds on the PI’s research progress in elucidating the diversity, molecular mechanisms, and biological roles of PTMs in archaea. Archaea provide valuable insights into PTM systems, as these microorganisms: i) share evolutionary connections with eukaryotes and are distinct from bacteria, and ii) serve as ideal models for understanding how cells adapt and thrive under extreme environmental conditions that typically damage DNA, RNA, and other biomolecules. This multi-project proposal is integrated around a common goal to address key gaps in understanding how PTM systems work in a coordinated manner to regulate microbial stress response mechanisms. Using the archaeon Haloferax volcanii as a model system, the proposal is focused on advancing knowledge of the biological roles and interactions of the ubiquitin-like proteasome system and lysine acetylation, with an emphasis on how these PTMs regulate DNA replication and repair (DNA/RNA metabolism and chromatin architecture), protein homeostasis (proteasomes), and cellular efficiency (biomolecular condensates). • Project 1 aims to enhance understanding of PTM-mediated regulation of protein-protein interactions (PPIs) and liquid-liquid phase separation (LLPS) of nucleases involved in DNA repair and cell viability. • Project 2 aims to address key gaps in knowledge regarding the function of proteasome assembly chaperones (PACs) in regulating proteasome assembly and activity, with a focus on the role of PTMs and the C-terminal HbYX motif in these processes. • Project 3 aims to deepen our understanding of Sir2-type sirtuin lysine deacetylases and their regulation of chromosome accessibility through their catalytic activity and interaction with thiol-sensing chromatin-binding proteins, such as OxsR. • Project 4 aims to provide insight into how PTM systems work together to control DNA topology, focusing on the interaction of Cdc48-type ATPases, ubiquitin-like ligation, and lysine acetylation in regulating Type 1A topoisomerases in archaea. The long-term goal of this proposal is to enhance our understanding of the interplay of PTM systems in microbial stress responses and translate this knowledge into applications that benefit human health. Project Number: 1R35GM161171-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: JULIE MAUPIN-FURLOW | Institution: UNIVERSITY OF FLORIDA, GAINESVILLE, FL | Award Amount: $383,750 | Activity Code: R35 | Study Section: Maximizing Investigators' Research Award - F Study Section[MRAF] View on NIH RePORTER: https://reporter.nih.gov/project-details/11257004