Gela G. Tevzadze

Ph.D., Genetics, Moscow State University, 1992
getevzad@midway.uchicago.edu

Research Interests

During meiosis in yeast, chromosome segregation is coordinated with packaging of meiotic products into spores via spindle pole bodies ( SPBs), which serve as sites for initiation of spindle formation as well as spore wall synthesis. Presently, little is known about the mechanism(s) which coordinate these two functions of SPBs. The focus of my research is to investigate the role of phospholipases and lipid-anchor proteins in the coupling of the meiotic divisions with gamete development in this organism. The role of SPO1 in coordinating the landmark events of meiosis is the major question addressed in these studies. SPO1 is the only gene known thus far to be required for meiotic, but not mitotic SPB duplication, suggesting Spo1 plays a regulatory rather than structural role in SPB duplication. SPO1encodes a protein highly similar to phospholipase B enzymes, known to be involved in signal transduction pathways. The properties of these enzymes and the behavior of spo1 mutants in meiosis have led us to suggest that Spo1 participates in a novel sporulation-specific signaling pathway to regulate SPB activities required for meiotic progression. Two other genes, CWP1 and SPO19 encoding GPI (lipid-anchored) proteins up-regulated late in meiosis, have been identified as high copy suppressors allowing spore formation in spo1 mutants. To explain these data we are testing the idea that Spo1 uses phosphatidylinositol (PI) as a substrate to generate Lyso-PI (a less hydrophobic derivative of PI), which is a potential second messenger molecule. Along with the decrease of PI, accumulation of Lyso-PI and fatty acid may also serve as signals regulating further progression of meiosis. GPI -proteins (normally upregulated in meiosis), when expressed from high-copy plasmids, may lower the concentration of PI, mimicking the effect of the Spo1 lipase activity on PI, its potential substrate.

To further dissect this genetic pathway(s), mutant suppressors of spo1 were sought and two non-allelic mutations (sms1 and sms2) isolated. Our data indicate each mutation plays both a positive and negative role during sporulation. The wild-type alleles of these mutants are required for both progression of meiosis in the presence of Spo1 and for blocking the process in its absence. Our working model proposes that wild-type Sms1p and Sms2p act as transmitters of a Spo1-generated signal derived from PI. The negative function in cells that lack Spo1 may be a part of a unique checkpoint-like control system, preventing spore formation in cells when SPB morphogenesis has not been executed properly. The SMS2 gene was cloned and identified as SPO73, a meiosis-specific locus up-regulated late in meiosis and shown previously to be required for spore wall formation but not for the MI and MII nuclear divisions. The Spo73 protein contains a high-potential iron-sulphur (HiPIP) domain, also found in two PI-specific kinases (Tor1 and Tor2) in S. cerevisiae. The sms2 point mutation (Gly108Arg) maps within the Fe-S domain, indicating that the domain is critical for both positive and negative functions of Spo73. The presence of the Fe-S domain in Spo73 and in kinases that act specifically in PI signaling suggests that this domain acts in sensing lipid signals. The identity of signal sensors/transmitters acting earlier (at MI and MII) is yet to be determined. The genetic studies outlined here provide a well-characterized background for continued analysis of the molecular activities and regulatory mechanisms that coordinate the meiotic divisions and gamete maturation. They connect a key process in meiosis, the coupling of nuclear division with packaging of haploid gametes, to conserved, well-characterized biochemical activities of phospholipases. In addition to dissecting the genetic control of gametogenic differentiation and providing new insights into the control of chromosome segregation, this research has important implications for how cell cycle programs interact with differentiation programs and how cellularization processes are regulated.

Recent Publications

Gela G. Tevzadze, Arcady R. Mushegian, and Rochelle Easton Esposito (1996). The SPO1 gene product required for meiosis in yeast has a high similarity to phospholipase B enzymes. Gene 177: 253-255

M. Joachimiak, G. Tevzadze, J. Podkowinski, R. Haselkorn and P. Gornicki (1997). Wheat cytosolic acetyl-CoA carboxylase complements an ACC1 null mutation in yeast. Proc. Natl. Acad. Sci. USA 94: 9990-9995

Nikolskaya T, Zagnitko O, Tevzadze G, Haselkorn R, Gornicki P (1999). Herbicide sensitivity determinant of wheat plastid acetyl-CoA carboxylase is located in a 400-amino acid fragment of the carboxyltransferase domain. Proc. Natl. Acad. Sci. U S A 96: 14647-14651

Gela G. Tevzadze, Hewson Swift and Rochelle Easton Esposito (2000). Spo1, a Phospholipase B Homolog, is Required for Spindle Pole Body Duplication During Meiosis in Saccharomyces cerevisiae. Chromosoma109: 72-85

M. Primig, R. M. Williams, E. A. Winzeler, G. G. Tevzadze, A. Conway, S. Hwang, R. W. Davis and R. Easton Esposito (2000). The Core Meiotic Transcriptome in Budding Yeasts. Nature Genetics26: 415-423.

O. Zagnitko, J. Jelenska, G. Tevzadze, R. Haselkorn, and P. Gornicki (2001). An Isoleucine/Leucine residue in a highly conserved region of the carboxyltransferase domain of acetyl-CoA carboxylase is critical for interaction with aryloxyphenoxypropionate and cyclohexanedione inhibitors. Proc. Natl. Acad. Sci. USA98: 6617-6622.