. The Origin Recognition Complex (ORC), heteromeric six-subunit protein complex, is essential for DNA replication. ORC's functions also extend beyond DNA replication. We found that the smallest of ORC subunit, Orc6 protein, is important for DNA binding and replication and has a structural homology with transcription factor TFIIB suggesting that it may target the formation of pre-replicative complex to the origins of DNA replication. Furthermore, we identified conserved motif within the C- terminus of Orc6 which is responsible for its interaction with the core ORC complex. Mutations in this motif affect the integrity of six-subunit ORC contributing to the pathogenesis of Meier-Gorlin syndrome (MGS) in humans. Orc6 also has a function in cytokinesis. It binds directly to septin complex via its Pnut subunit, stimulates the intrinsic GTPase activity of the Drosophila septin complex and greatly facilitates septin filament formation. The overall goal of our proposal is to characterize the mechanism of Orc6 functions in DNA replication and cytokinesis using Drosophila as a model system. Our experiments are designed to answer important questions about the structure of Orc6, its functions in replication and its role in septin polymerization. Drosophila model systems will be used to analyze the effects of naturally occurring and structure-guided targeted mutations of human Orc6 in diverse protein functions. Because ORC is conserved in evolution, what we learn about its functions in Drosophila will be valuable to our understanding of ORC's functions in other eukaryotes. A better understanding of how ORC functions in Drosophila will provide insights into ORC's behavior in mammals and provide clues as to how its misregulation leads to cancer.

Public Health Relevance

The goal of our proposal is to define the role of Origin Recognition Complex (ORC) during the cell cycle in eukaryotes. Because ORC is conserved in evolution, what we learn about its structure and functions will provide insights as to how its misregulation leads to cancer. An understanding of the molecular events involved in the initiation of replication and cell cycle progression will provide a basis for ultimately controlling these processes.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cellular Signaling and Regulatory Systems Study Section (CSRS)
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Reddy, Michael K
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University of Alabama Birmingham
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Akhmetova, Katarina; Balasov, Maxim; Svitin, Anton et al. (2018) Phosphorylation of Pnut in the Early Stages of Drosophila Embryo Development Affects Association of the Septin Complex with the Membrane and Is Important for Viability. G3 (Bethesda) 8:27-38
Akhmetova, K A; Chesnokov, I N; Fedorova, S A (2018) [Functional Characterization of Septin Complexes]. Mol Biol (Mosk) 52:155-171