Professor, Eppley InstitutePhone: 402-559 -7717
E-mail: Youri Pavlov
M.S. Department of Genetics, Leningrad State University, USSR; Genetics
Ph.D. Department of Genetics, Leningrad State University, USSR; Genetics
Our laboratory is interested in the mechanisms of maintenance of genome stability during replication, repair, recombination, transcription and editing. In particular, we want to understand the mechanisms of global and region-specific control of mutagenesis in different cell types and along chromosomes in eukaryotes.
Evolutionary determined mutation rates depend on levels of endogenous and environmental DNA damage and editing, the efficiency of the repair and high fidelity of chromosomal replication. Impairment of DNA and chromatin metabolism often enhances mutation rates and drastically decreases viability due to cancer onset. Examples are defects in: 8-oxo-dGTPase; proofreading by DNA polymerases Δ and Ε in mice and humans; in mismatch repair in families with hereditary nonpolyposis colorectal cancer; in DNA lesion bypass in XP-V patients in humans. It is also emerges that elevated levels of DNA editing enzymes are mutagenic and can cause cancer.
Being deleterious, global mutators cannot account for evolutionary and developmental processes in eukaryotes in the situations when high level of mutagenesis is desired. Current evidence suggests that mutation rates differ significantly along the genome. The most striking example of such variation comes from the immunology field. In specialized cells responsible for antibody production, the variable regions of immunoglobulin genes have six orders of magnitude higher mutation rates than
other genes. An example of human disease associated with mutability of selected genes is fragile X and Huntington disease, which depends on the expansion of triplet repeats in a certain region of the chromosome.
Recently, it was found that, in addition to faithful repair, human cells quite astonishingly are equipped with proteins that act in the opposite way and introduce damage into their own DNA or RNA. This provides an opportunity to create variability "on demand" but poses a threat to genome integrity in case of faulty regulation of intrinsic mutators. Most of the important players of the systems of this newly recognized type of diversification are members of AID/APOBEC family of DNA/RNA cytosine deaminases indispensable for humoral and innate immunity. They introduce site-directed damage to specific regions or species of DNA but, if improperly regulated, can damage other chromosomal loci causing many single as well as clustered mutations and promoting cancer.
We are creating novel systems to study mutation signatures of DNA polymerases and APOBEC enzymes on DNA templates representing critical eukaryotic genes, e.g. immunoglobulins or cancer susceptibility genes. Inventory of mutational signatures of individual genome maintenance components enables us to find these signatures in mutational spectra of selected human genes critical for a disease. We investigate the mechanisms of differential mutability by identifying genes or chromosome regions affecting the distribution of mutation events along the chromosomes in trans or cis positions. We use several traditional molecular genetics model objects, primarily baker’s yeast Saccharomyces cerevisiae. We use Next Generation Sequencing for the characterization of the distribution of mutations arising when replication is inaccurate or when DNA editing is overly extensive. We initiated similar studies with human cell lines.
Selected Publications (see PubMed for Pavlov YI)