Igor Chesnokov, Ph.D.
Assistant Professor, Department of Biochemistry and Molecular Genetics
Areas of Focus: The study of the molecular mechanisms of DNA replication and cell cycle progression in eukaryotes.
Our laboratory studies the molecular mechanisms of DNA replication and cell cycle progression in eukaryotes. The initiation of DNA replication in higher eukaryotes occurs at thousands of sites along chromosomes. The utilization of such sites in multicellular organisms changes during development and this process is known to affect both gene expression programs and chromosome folding. The Origin Recognition Complex (ORC) is a critical component for DNA replication. ORC binds to DNA at replication origin sites and serves as a scaffold for assembly of other key initiation factors. How these factors eventually lead to a melting of the duplex strands and an engagement of the DNA polymerase alpha is still unknown. A deeper understanding of how the cell cycle machinery triggers initiation and couples this event to signal transduction pathways requires a finer dissection of the initiation process.
ORC's functions extend beyond DNA replication. The complex has been implicated in chromosome condensation and the control of M phase events. Recently we have established that Orc6, the smallest subunit of Origin Recognition Complex (ORC) which is important for DNA replication, is also essential for cytokinesis in Drosophila. Orc6 is found at the cell membranes and interacts with the septin protein Pnut, which is part of the Drosophila septin complex. The Pnut-dependent binding of Orc6 increases the intrinsic GTPase activity of the Drosophila septin complex, while in the absence of GTP it enhances septin complex filament formation. These results suggest an active role for Orc6 in septin complex function. Research projects in our lab address a number of the questions, including: how do septins interact with each other to assemble into functional complex and further into large multimeric filaments? How does septin complex in Drosophila bind and hydrolyze a nucleotide and what motifs are responsible for this function? What is the role of post translational modification of the Pnut protein for septin complex functions during Drosophila development? What is the role of the septin interacting protein, Orc6, in septin complex functions?
For our studies we use Drosophila as a model system as well as mammalian cell lines. Working with Drosophila proved to be advantageous for these studies as it allows the use of both biochemical and genetic methods and also permits insights into the developmental as well as tissue specific aspects of replication control. An understanding of the molecular events involved in the initiation of replication and cytokinesis will provide a basis for ultimately controlling these processes. Such control might lead to rationally designed therapies for cancer and may provide the means for regenerating cells lost due to aging, disease or injury.
Igor Chesnokov completed his undergraduate studies and received his Ph.D. degree in Biochemistry at Leningrad State University (Russia) in 1992. He did his post-doctoral work at the University of California in Berkeley and Davis. He joined the department of Biochemistry and Molecular Genetics at UAB in 2002.