Associate Professor, Eppley Institute
M.S., St. Petersburg State University, Russia, 1992, Genetics
Ph.D., St. Petersburg State University, Russia, 1997, Genetics
Mechanisms of mutagenesis mediated by translesion synthesis DNA polymerases
Summary of Research
Our laboratory is interested in the mechanisms controlling genome stability in eukaryotic cells, particularly in the functions of DNA polymerases in DNA replication, repair and chromosome segregation control.
Proper transmission of genetic information to daughter cells requires faithful replication of chromosomes followed by their accurate segregation during cell division. Errors during replication or repair of DNA damage result in mutations, while errors in chromosome segregation result in aneuploidy. Both types of genome instability are nearly ubiquitous features of human cancers.
There are two ongoing projects in the laboratory, both of which use the yeast Saccharomyces cerevisiae as a model experimental system.
- Role of DNA polymerases in chromosome stability control. A network of checkpoint mechanisms exists to ensure that chromosome segregation does not occur until DNA replication is complete and damaged DNA is repaired. Several mutations in DNA polymerases or their accessory proteins have been shown to affect both DNA replication checkpoint and cellular response to DNA damage. This suggests that enzymes that actually perform DNA synthesis might play an active role in the control of chromosome segregation. Chromosome loss and/or nondisjunction is an important potential consequence of uncoordinated DNA synthesis and chromosome segregation. We are developing a novel system that allows direct selection for chromosome nondisjunction events in yeast and are planning to use this system to identify DNA polymerase mutations that lead to an increased rate of chromosome nondisjunction.
- Mechanisms of mutagenesis mediated by “lesion bypass” DNA polymerases. Cellular DNA is continuously damaged by endogenous and exogenous genotoxicants. Although cells possess specialized repair pathways that remove various types of damage, DNA damage occurs throughout the cell cycle, including during the S-phase. The replication machinery, therefore, occasionally encounters damaged DNA templates, which creates obstacles for DNA replication. The last several years have seen the discovery of DNA polymerases that have the ability to bypass lesions in template DNA that block replicative DNA polymerases. Although the translesion synthesis helps the cells to overcome the replication block, mutations are often generated as a result of inaccurate DNA synthesis by the lesion bypass polymerases. We are studying the mechanisms that lead to the recruitment of these polymerases to the replication fork and regulate the extent of their participation in genome replication.
Phone: 402-559 -7694
E-mail: Polina Shcherbakova