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Faculty Lecture Series


When

Wednesday, October 14, 2009
5 PM - 6 PM

Where

Valerie Timken Amphitheater
Green Hospital

Who

John Tainer, Ph.D.
Professor, Department of Molecular Biology
Member, The Skaggs Institute for Chemical Biology

Topic

"DNA repair machines are genome guardians that provide predictive biology and insights for cancer interventions"
  DNA integrity is critical to cell survival and resistance to cancer and aging. Such genome maintenance requires multi-protein DNA repair machinery evolved to avoid release of toxic intermediates and to coordinate repair with replication and transcription. Thus interpreting biological responses to DNA damage requires a focus on macromolecular assembles not individual enzymes. In fact, enzyme-based disease interventions are relatively unpredictable, due to the complex interplay of many independent variables. In contrast, protein assemblies direct biological outcomes and coordinate pathway choices. Exemplary assemblies controlling nucleotide excision repair of bulky DNA damage and initiating repair of double-strand breaks show how molecular shape conveys information, allows coordination, and aids prediction in cell biology. Extreme mass action, multi-protein allostery, and keystone complexes reveal how macromolecules orchestrate DNA repair in concert with transcription and replication. The combination of solution and crystallographic structures with mutational and genetic analyses of dynamic DNA repair machinery provides paradigm-shifting information for prediction and intervention into biological and medical outcomes.

Selected Publications

  Hopfner, K.P., Karcher, A., Shin, D.S., Craig, L., Arthur, L.M., Carney, J.P., and J.A. Tainer. 2000. Rad50 ATPase: ATP-driven control in DNA double-strand break repair & the ABC-ATPase superfamily, Cell 101: 789-800.
  Fan, L., Fuss, J.O., Cheng, Q.J., Arvai, A.S., Hammel M., Roberts, V.A., Cooper; P.K., Tainer, J.A. (2008) XPD helicase structures and activities: insights into the cancer and aging phenotypes from XPD mutations. Cell133:789-800.
  Williams, RS, Moncalian, G. Williams, JS, Yamada, Y, Limbo, O, Shin, DS, Groocock, LM, Cahill, D, Hitomi, C, Guenther, G, Moiani, D, Carney, JP, Russell, P, Tainer JA (2008) Mre11 Dimers Coordinate DNA End Bridging and Nuclease Processing in Double Strand Break Repair, Cell135:97–109.
  Tubbs J.L., Latypov V., Kanugula S., Butt A., Melikishvili M., Kraehenbuehl R., Fleck O., Marriott A., Watson A.J., Verbeek B., McGown G., Thorncroft M., Santibanez-Koref M.F., Millington C., Arvai A.S., Kroeger M.D., Peterson L.A., Williams D.M., Fried M.G., Margison G.P., Pegg A.E., and J.A.Tainer. 2009. Flipping of alkylated DNA damage bridges base and nucleotide excision repair. Nature 459:808-813.
  Williams, R.S., Dodson, G.E., Limbo, O., Yamada, Y., Williams, J.S., Guenther, G., Classen, S., Glover, J.N.M., Iwasaki, H., Russell, P., and Tainer, J.A. (2009). Nbs1 flexibly tethers Ctp1 and Mre11-Rad50 to coordinate Double-Strand Break Processing and Repair, Cell 139: in press.