Journal article
Two-step mechanism involving active-site conformational changes regulates human telomerase DNA binding
CG Tomlinson, AL Moye, JK Holien, MW Parker, SB Cohen, TM Bryan
Biochemical Journal | PORTLAND PRESS LTD | Published : 2015
DOI: 10.1042/BJ20140922
Abstract
The ribonucleoprotein enzyme telomerase maintains telomeres and is essential for cellular immortality in most cancers. Insight into the telomerase mechanism can be gained from syndromes such as dyskeratosis congenita, in which mutation of telomerase components manifests in telomere dysfunction. We carried out detailed kinetic and thermodynamic analyses of wild-type telomerase and two disease-associated mutations in the reverse transcriptase domain. Differences in dissociation rates between primers with different 3′ ends were independent of DNA affinities, revealing that initial binding of telomerase to telomeric DNA occurs through a previously undescribed two-step mechanism involving enzyme ..
View full abstractGrants
Awarded by Cancer Council NSW project
Awarded by Cancer Institute NSW
Funding Acknowledgements
This work was supported by the Cancer Council NSW project grant [grant number RG12-02], the Cancer Institute NSW career development and support fellowship [grant number 11/CDF/3-05 (to T.M.B.)] and a Priority Driven Young Investigator grant co-funded by the Cancer Australia and Cure Cancer Australia Foundation (to C.G.T.). Infrastructure support from the National Health and Medical Research Council (NHMRC) Independent Research Institutes Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Support Program to St Vincent's Institute are gratefully acknowledged. J.K.H is a joint Cure Cancer-Leukaemia Foundation Postgraduate Fellow and M.W.P. is a NHMRC Senior Principal Research Fellow.