Kirill Lobachev, Associate Professor
About Kirill Lobachev
Ph.D., Biology, St. Petersburg State University
Office: Parker H. Petit Biotechnology (IBB) 2303
Eukaryotic chromosomes must be accurately maintained, duplicated and segregated during mitotic and meiotic divisions to guarantee inheritance of the correct genetic information by the daughter cells. However, occasionally genome integrity can be compromised: chromosomes break and rearrange which can cause drastic changes in the way how genes are expressed. This type of genetic instability is a causative factor in the development of many hereditary diseases and cancers in humans. On the other hand, the ability of chromosomes to undergo breakage and rearrangements promotes genetic variations that contribute to species polymorphisms and evolution.
Multiple environmental and intracellular factors such as ionizing radiation, UV light or reactive oxygen species are well-established damaging agents that can fracture chromosomes at any position and trigger chromosomal abnormalities. Nevertheless, work over recent years has established that breaks along the chromosomes do not occur randomly but rather often coincide with the regions containing repetitive elements capable of adopting non-canonical DNA secondary structures. The enigmatic discovery that DNA repeats which can be inherited or occur de novo are a very powerful source of the breakage and rearrangements adds new perspective to our understanding of the origin of human pathology, polymorphism and evolution. Why breaks happen, what genetic and environmental factors contribute to fragility, what are the consequences of these types of breaks for the integrity of the eukaryotic genome? These are the questions that we are trying to address using yeast as a model eukaryotic organism in my laboratory. Currently, three sequence motifs that can adopt different secondary structures, namely, hairpin and cruciform-forming inverted repeats, G-quadruplex-forming repeats and GAA/TTC tracts prone for triplex formation are under our investigation. I believe that underlying mechanisms of repeat-mediated breakage uncovered in yeast can be extrapolated to the studies of chromosomal dynamics of higher eukaryotes including humans.
Shishkin A.A., Voineagu I., Matera R., Cherng N., Chernet B.T., Krasilnikova M.M., Narayanan V., Lobachev K.S., Mirkin S.M. (2009) "Large-scale expansions of Friedreich’s ataxia GAA repeats in yeast." Molecular Cell 35(1): 82-92.
Voineagu I., Narayanan V., Lobachev K.S., Mirkin S.M. (2008) "Replication stalling at unstable inverted repeats: interplay between DNA hairpins and fork stabilizing proteins", PNAS 105: 9936-9941 (Highlighted in Discovery magazine and Nature journal 2008, 454:371)
Kim H-M., Narayanan V. Mieczkowski P.A., Petes T.D., Krasilnikova M.M., Mirkin S.M. and Lobachev K.S. (2008) "Chromosome fragility at GAA/TTC tracts depends on repeat orientation and requires mismatch repair" EMBO journal 27:2896-906
VanHulle K., Lemoine F. J., Narayanan V., Downing B., Hull K., McCullough C., Bellinger M., Lobachev K., Petes T. D., Malkova A. (2007) "Inverted DNA repeats channel repair of distant double-strand breaks into chromatid fusions and chromosomal rearrangements" Molecular and Cellular Biology 27: 2601-2614
Lobachev K.S., Rattray A., Narayanan V. (2007) "Hairpin- and cruciform-mediated chromosome breakage: causes and consequences in eukaryotic cells", Frontiers in Bioscience 12: 4208-4220
Narayanan V., and Lobachev K.S. (2007) "Intrachromosomal amplification triggered by hairpin-capped breaks is homologous recombination-dependent and non-homologous end-joining-independent", Cell Cycle 6: 1814-1818
Narayanan V., Mieczkowski P., Kim H-M., Petes T.D., Lobachev K.S. (2006) "The pattern of gene amplification is determined by chromosomal location of hairpin-capped breaks" Cell 125:1283-1296 ("Sigma Xi Best Paper", Featured in the same issue of Cell)
Lemoine F, Degtyareva N.P., Lobachev K.S., Petes T. D. (2005) "Chromosomal translocations in yeast induced by low levels of DNA polymerase: a model for chromosome fragile sites", Cell 120: 587-598 (Featured in the same issue of Cell and on the cover of journal),