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Insights into diseases of human telomerase from dynamical modeling
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. (Flores)
2013 (English)In: / [ed] Russ Altman, 2013, 200-211 p.Conference paper (Refereed)
Abstract [en]

Mutations in the telomerase complex disrupt either nucleic acid binding or catalysis, and are the cause of numerous human diseases. Despite its importance, the structure of the human telomerase complex has not been observed crystallographically, nor are its dynamics understood in detail. Fragments of this complex from Tetrahymena thermophila and Tribolium castaneum have been crystallized. Biochemical probes provide important insight into dynamics. In this work we summarize evidence that the T. castaneum structure is Telomerase Reverse Transcriptase. We use this structure to build a partial model of the human Telomerase complex. The model suggests an explanation for the structural role of several disease-associated mutations. We then generate a 3D kinematic trajectory of telomere elongation to illustrate a "typewriter" mechanism: the RNA template moves to keep the end of the growing telomeric primer in the active site, disengaging after every 6-residue extension to execute a "carriage return" and go back to its starting position. A hairpin can easily form in the primer, from DNA residues leaving the primer-template duplex. The trajectory is consistent with available experimental evidence. The methodology is extensible to many problems in structural biology in general and personalized medicine in particular.

Place, publisher, year, edition, pages
2013. 200-211 p.
National Category
Biochemistry and Molecular Biology
URN: urn:nbn:se:uu:diva-187591DOI: 10.1142/9789814447973_0020ISBN: 978-981-4447-97-3OAI: oai:DiVA.org:uu-187591DiVA: diva2:575247
Pacific Symposium on Biocomputing
eSSENCE - An eScience CollaborationSwedish Research Council
Available from: 2012-12-08 Created: 2012-12-08 Last updated: 2013-11-21Bibliographically approved

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Flores, Samuel
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Department of Cell and Molecular Biology
Biochemistry and Molecular Biology

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