Education/Training College Degree
B.A. (Honors) - University of Pennsylvania
Ph.D. - University of California, Los Angeles
Post-Doctoral Fellow - Harvard Medical School
My research centers on the structure and function of protein complexes crucial to chromosomal integrity and RNA processing. We currently have two main projects in the laboratory:
Characterization of the structure and function of the helicase Mtr4p from Saccharomyces cerevisiae. Mtr4p is thought to assist in both processing and degradation of nuclear RNAs by a large exonucleolytic complex called the exosome. The processing function is crucial for producing functional forms of, for example, the 5.8S ribosomal RNA (rRNA). Without appropriate processing, ribosome biogenesis is compromised and protein synthesis ceases. In addition, the degradation function of this system removes processing intermediates and prevents aberrant RNAs from traveling to the cytoplasm. Our main focus is on the helicase activity of Mtr4p, and how this activity is coordinated with the exonucleolytic activity of the exosome.
Structural and functional studies of the human MutY homologue (hMYH). In the absence of appropriate repair, oxidative damage to DNA by endogenous or exogenous reactive oxygen species can cause permanent cell damage that ultimately promotes cancer due to the presence of oxidized bases that errantly template new DNA synthesis. MYH-associated polyposis (MAP) is a recently described colorectal adenoma/carcinoma predisposition syndrome that is associated with expression of a mutant hMYH protein. hMYH is a glycosylase that excises misincorporated bases resulting from oxidative lesions on the parent DNA strand. In particular, adenine and 2-hydroxyadenine are often erroneously incorporated across the mutagenic lesion 8-oxo-7,8-dihydrodeoxyguanine (8-oxoG) during DNA replication. These replication errors cause G:C to T:A transversions that can severely impair the function of oncogenic proteins that control cellular proliferation in the colon such as Adenomatous polyposis coli (APC) or K-ras. In patients with MYH-associated polyposis (MAP), there are no inherited mutations in the APC gene, but there are somatic mutations in either APC or K-ras in colorectal tumors. The DNA repair activity of hMYH is linked both physically and functionally to DNA replication, mismatch repair, the base-exision repair (BER) pathway, and cell cycle checkpoint control. However, the details regarding how these physical interactions control both hMYH activity and the activities of its protein binding partners are not well understood.
Dimeka Patterson - Research Technician and Lab Manager
Jade Bernstein - Graduate Student
Paz Luncsford - Graduate Student
Charpentier TH, Wilder PT, Liriano MA, Varney KM, Pozharski E, Mackerell AD Jr, Coop A, Toth EA, Weber DJ. (2008) Divalent Metal Ion Complexes of S100B in the Absence and Presence of Pentamidine. J. Mol. Biol. 382(1), 56-73.
Bernstein J, Patterson DN, Wilson GM, Toth EA. (2008). Characterization of the essential activities of Saccharomyces cerevisiae Mtr4p, A 3'â?'5' helicase partner of the nuclear exosome. J. Biol. Chem., 283(8), 4930-4942.
Fialcowitz-White, E.J., Brewer, B.Y., Ballin, J.D., Willis, C.D., Toth, E.A., and Wilson, G.M. (2007). Specific protein domains mediate cooperative assembly of HuR oligomers on AU-rich mRNA-destabilizing sequences. J. Biol. Chem., 282(29), 20948-20959.
Toth, E.A., Li, Y., Sawaya, M.R., Cheng, Y., and Ellenberger, T.(2003). The crystal structure of the bifunctional primase-helicase of bacteriophage T7. Mol Cell., 12(5), 1113-1123.
Silvian, L.F., Toth, E.A., Pham, P., Goodman, M.F., and Ellenberger, T.(2001). Crystal structure of a DinB family error-prone DNA polymerase from Sulfolobus solfataricus. Nat Struct Biol., 8(11), 984-989.
Toth, E.A., and Yeates, T.O. (2000) The structure of adenylosuccinate lyase, an enzyme with dual activity in the de novo purine biosynthetic pathway. Structure, 8, 163-174.
Toth, E.A., Worby, C., Dixon, J.E., and Yeates, T.O.(2000) The crystal structure of adenylosuccinate lyase from Pyrobaculum aerophilum reveals an intracellular protein with three disulfide bonds. JMB, 301, 433-450.
Colovos, C., Toth, E.A., and Yeates, T.O. (2000) Evaluation of phase accuracy via topological and geometric analysis of electron density maps. Acta Crystallographica D56, 1421-1429.