个人简介

B.Sc. (Bachelor of Science) Ph.D. (Doctor of Philosophy)

研究领域

Molecular Biology and Disease Cell Signalling and Structure

The Williams lab applies structural biology approaches to determine molecular mechanisms of genomic instability and cancer. A main interest in the lab is to understand the molecular basis for key steps in the homologous recombination repair (HRR) pathway. HRR plays a critical role in maintaining genomic stability by accurately repairing DNA double strand breaks and inter-strand crosslinks, the most toxic forms of DNA damage, as well as damaged replication forks. The importance of HRR for protecting against cancer is highlighted by inherited mutations in HRR genes (including BRCA1, BRCA2, and the RAD51 paralogs) that predispose to breast and ovarian cancers. Using hybrid structural techniques, with a focus on combining small-angle X-ray scattering with macromolecular X-ray crystallography, we can determine the structural basis for protein-protein and protein-DNA interactions, as well as the effect of ATP binding and hydrolysis on macromolecular conformational changes and assembly states. Using structure-based insights we design mutations to perturb interactions and activities, which are then used in biochemical and functional assays to inform the underlying biology. Furthermore, our structures and approaches provide a molecular framework that can be used to both understand the effect of disease associated mutations, and to guide the design of future cancer therapies. The Williams lab is looking for suitable PhD candidates or postdoctoral fellows interested in research projects to determine molecular mechanisms of DNA double strand break repair. Please email gareth.williams2@ucalgary.ca if you are interested.

近期论文

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A novel Fanconi anaemia subtype associated with a dominant-negative mutation in RAD51.Ameziane N, May P, Haitjema A, van de Vrugt HJ, van Rossum-Fikkert SE, Ristic D, Williams GJ, Balk J, Rockx D, Li H, Rooimans MA, Oostra AB, Velleuer E, Dietrich R, Bleijerveld OB, Maarten Altelaar AF, Meijers-Heijboer H, Joenje H, Glusman G, Roach J, Hood L, Galas D, Wyman C, Balling R, den Dunnen J, de Winter JP, Kanaar R, Gelinas R, Dorsman JC. An AAA+ ATPase Clamshell Targets Transposition.Tsai CL, Williams GJ, Perry JJ, Tainer JA.Cell. 2015; 162(4):701-3. Envisioning the dynamics and flexibility of Mre11-Rad50-Nbs1 complex to decipher its roles in DNA replication and repair.Lafrance-Vanasse J, Williams GJ, Tainer JA.Progress in biophysics and molecular biology. 2015; 117(2-3):182-93. NIHMSID: NIHMS653508 Rare key functional domain missense substitutions in MRE11A, RAD50, and NBN contribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case-control mutation-screening study.Damiola F, Pertesi M, Oliver J, Le Calvez-Kelm F, Voegele C, Young EL, Robinot N, Forey N, Durand G, Vallée MP, Tao K, Roane TC, Williams GJ, Hopper JL, Southey MC, Andrulis IL, John EM, Goldgar DE, Lesueur F, Tavtigian SV.Breast cancer research : BCR. 2014; 16(3):R58. Structural insights into NHEJ: building up an integrated picture of the dynamic DSB repair super complex, one component and interaction at a time.Williams GJ, Hammel M, Radhakrishnan SK, Ramsden D, Lees-Miller SP, Tainer JA.DNA repair. 2014; 17:110-20. NIHMSID: NIHMS591970 Interfacial residues promote an optimal alignment of the catalytic center in human soluble guanylate cyclase: heterodimerization is required but not sufficient for activity.Seeger F, Quintyn R, Tanimoto A, Williams GJ, Tainer JA, Wysocki VH, Garcin ED.Biochemistry. 2014; 53(13):2153-65. ATP-driven Rad50 conformations regulate DNA tethering, end resection, and ATM checkpoint signaling.Deshpande RA, Williams GJ, Limbo O, Williams RS, Kuhnlein J, Lee JH, Classen S, Guenther G, Russell P, Tainer JA, Paull TT.The EMBO journal. 2014; 33(5):482-500. Mechanistic insights into the role of Hop2-Mnd1 in meiotic homologous DNA pairing.Zhao W, Saro D, Hammel M, Kwon Y, Xu Y, Rambo RP, Williams GJ, Chi P, Lu L, Pezza RJ, Camerini-Otero RD, Tainer JA, Wang HW, Sung P.Nucleic acids research. 2014; 42(2):906-17. DNA conformations in mismatch repair probed in solution by X-ray scattering from gold nanocrystals.Hura GL, Tsai CL, Claridge SA, Mendillo ML, Smith JM, Williams GJ, Mastroianni AJ, Alivisatos AP, Putnam CD, Kolodner RD, Tainer JA.Proceedings of the National Academy of Sciences of the United States of America. 2013; 110(43):17308-13. Functional attributes of the Saccharomyces cerevisiae meiotic recombinase Dmc1.Busygina V, Gaines WA, Xu Y, Kwon Y, Williams GJ, Lin SW, Chang HY, Chi P, Wang HW, Sung P.DNA repair. 2013; 12(9):707-12. NIHMSID: NIHMS485514 Insights into FlaI functions in archaeal motor assembly and motility from structures, conformations, and genetics.Reindl S, Ghosh A, Williams GJ, Lassak K, Neiner T, Henche AL, Albers SV, Tainer JA.Molecular cell. 2013; 49(6):1069-82. NIHMSID: NIHMS437276 ABC ATPase signature helices in Rad50 link nucleotide state to Mre11 interface for DNA repair.Williams GJ, Williams RS, Williams JS, Moncalian G, Arvai AS, Limbo O, Guenther G, SilDas S, Hammel M, Russell P, Tainer JA.Nature structural & molecular biology. 2011; 18(4):423-31. NIHMSID: NIHMS273693 Mre11-Rad50-Nbs1 conformations and the control of sensing, signaling, and effector responses at DNA double-strand breaks.Williams GJ, Lees-Miller SP, Tainer JA.DNA repair. 2010; 9(12):1299-306. NIHMSID: NIHMS249331 Achieving fidelity in homologous recombination despite extreme complexity: informed decisions by molecular profiling.Rambo RP, Williams GJ, Tainer JA.Molecular cell. 2010; 40(3):347-8. NIHMSID: NIHMS250111 Enhancement of RAD51 recombinase activity by the tumor suppressor PALB2.Dray E, Etchin J, Wiese C, Saro D, Williams GJ, Hammel M, Yu X, Galkin VE, Liu D, Tsai MS, Sy SM, Schild D, Egelman E, Chen J, Sung P.Nature structural & molecular biology. 2010; 17(10):1255-9. NIHMSID: NIHMS231461 A charged performance by gp17 in viral packaging.Williams RS, Williams GJ, Tainer JA. Cell. 2008; 135(7):1169-71. Promotion of homologous recombination and genomic stability by RAD51AP1 via RAD51 recombinase enhancement.Wiese C, Dray E, Groesser T, San Filippo J, Shi I, Collins DW, Tsai MS, Williams GJ, Rydberg B, Sung P, Schild D.Molecular cell. 2007; 28(3):482-90. NIHMSID: NIHMS34042 Structure of the heterotrimeric PCNA from Sulfolobus solfataricus.Williams GJ, Johnson K, Rudolf J, McMahon SA, Carter L, Oke M, Liu H, Taylor GL, White MF, Naismith JH.Acta crystallographica. Section F, Structural biology and crystallization communications. 2006; 62(Pt 10):944-8. Structure and function of both domains of ArnA, a dual function decarboxylase and a formyltransferase, involved in 4-amino-4-deoxy-L-arabinose biosynthesis.Williams GJ, Breazeale SD, Raetz CR, Naismith JH.The Journal of biological chemistry. 2005; 280(24):23000-8. NIHMSID: UKMS47402