Our research focuses on the functional relationship between chromosome organization on the microscopic level and DNA transitions on the molecular level. Changes in chromosome structure occur in parallel with DNA events at all stages of the cell cycle. Transmission of an intact genome depends on coordination between these levels. Defects in genome stability are associated with cancer, aging and birth defects such as Down syndrome.
We are investigating the interplay between chromosome structure and DNA recombination during the meiotic cell cycle. Meiosis is characterized by a series of well-defined transitions: During the prophase of meiosis I, homologous chromosomes undergo pairing, organize along proteinaeous axes, and become connected via the synaptonemal complex (SC). In parallel, recombination is initiated by introduction of numerous double strand breaks (DSBs) which are processed into crossovers. Crossovers establish a physical connection between homologous chromosomes thereby ensuring their faithful segregation.
Crossovers are non-randomly distributed along the genome, suggesting a mechanism of genome-wide coordination. We have previously shown that crossover sites become designated when the broken chromosome first interacts with its partner homolog. This indicates that crossover sites are designated (i) prior to and independent of SC formation and (ii) at an earlier stage than predicted by classical models of homologous recombination. The ZMM group of proteins mediates both crossover-specific strand invasion and SC polymerization, suggesting functional linkage between these key events.
We are using cytological, biochemical and functional genomics approaches to analyze roles of the SC and SC-associated proteins in chromosomal exchange. We are further investigating the surveillance mechanisms that couple DSB processing to the progression of the meiotic cell cycle.
Perry, J., Kleckner, N. & Börner, G.V. (2005). Bioinformatic analyses implicate the collaborating meiotic crossover/chiasma proteins, Zip2, Zip3 and Spo22/Zip4, in ubiquitin labeling. Proc. Natl. Acad. Sci. USA (in press).
Börner, G.V., Kleckner, N. & Hunter, N. (2004). Crossover/noncrossover differentiation, synaptonemal complex formation and regulatory surveillance at the leptotene/zygotene transition of meiosis. Cell 117:29-45.
Hunter, N., Börner, G.V., Lichten, M. & Kleckner, N. (2001). Gamma-H2AX illuminates meiosis. Nature Genet. 27, 236-238.
Börner, G.V. , Zeviani, M., Tiranti, V., Carrara, F., Hoffmann, S., Gerbitz, K.D., Lochmüller, H., Pongratz, D., Klopstock, T., Melberg, A., Holme, E. & Pääbo, S. (2000). Decreased aminoacylation of mutant tRNAs in MELAS but not in MERRF patients. Hum. Mol. Genet. 9, 467-475.
Börner, G.V., Yokobori, S., Mörl, M., Dörner, M., & Pääbo, S. (1997). RNA editing in metazoan mitochondria: staying fit without sex. FEBS Letters 409, 320-324.
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