Faculty Research Page
Walter and Ruth Schubert Family Chair, Professor of Biochemistry, Biophysics and Structural BiologyLab Homepage: https://sites.google.com/site/kcollinslab/
Collins lab interests center on the eukaryotic ribonucleoprotein reverse transcriptase telomerase, cellular RNP biogenesis pathways, and non-coding RNA.
Telomerase RNP biogenesis, activity and regulation
The reverse transcriptase telomerase adds simple-sequence repeats to chromosome ends by copying a template within its integral RNA subunit. New telomeric repeat synthesis by telomerase can compensate for the loss of repeats that occurs with each round of genome replication, but how the balance of telomere lengthening and telomere erosion is monitored and how this balance is regulated remain unknown. We study telomerases both as recombinant enzymes, to understand the unique structure and dynamic nucleic acid handling properties of the ribonucleoprotein complex, and also in cells, to understand the complex pathways for active RNP biogenesis and regulation at telomeres.
Many of our studies focus on the protein-protein and protein-nucleic acid recognition specificities and conformational changes that underlie the telomerase catalytic cycle of short repeat synthesis. Exploiting the ciliate Tetrahymena as a model system, we accomplished the purification, characterization and reconstitution of a complete, biologically functional telomerase holoenzyme. Ongoing studies pursue the delineation of individual telomerase holoenzyme subunit functions. In parallel we are using biochemical, molecular and cellular assays to investigate the assembly and regulation of human telomerase in embryonic stem cells and cancer cells.
We use diverse approaches from the level of structural biology to biochemical characterization of macromolecular interactions to genome engineering.
New functions for non-coding RNA
We have been applying our insights from studies of telomerase RNA to more general investigations of non-coding RNA biogenesis and function. In human cells we have discovered new RNA processing pathways and RNA functions in stress response and innate immunity. In Tetrahymena we continue to discover new mechanisms by which nuclear-localized Piwi proteins influence gene expression and epigenetic inheritance.
Wu RA, Dagdas YS, Yilmaz ST, Yildiz A, Collins K. Single-molecule imaging of telomerase reverse transcriptase in human telomerase holoenzyme and minimal RNP complexes. eLife in press (2015).
Hockemeyer D, Collins K. Control of human telomerase action at telomeres. NSMB in press (2015).
Vogan JM, Collins K. Dynamics of human telomerase holoenzyme assembly and subunit exchange across the cell cycle. JBC 290: 21320-35 (2015).
Upton HE, Hong K, Collins K.Direct single-stranded DNA binding by Teb1 mediates the recruitment of Tetrahymena telomerase to telomeres. MCB 34: 4200-12 (2014).
Wu RA, Collins K. Sequence specificity of human telomerase. PNAS 111: 11234-5 (2014).
Sexton AN, Regalado SG, Lai CS, Cost GJ, O'Neil CM, Urnov FD, Gregory PD, Jaenisch R, Collins K, Hockemeyer D. Genetic and molecular identification of three human TPP1 functions in telomerase action: Recruitment, activation, and homeostasis set-point regulation. Genes Dev. 28: 1885-99 (2014).
Katibah GE, Qin Y, Sidote DJ, Yao J, Lambowitz AM, Collins K. Broad and adaptable RNA structure recognition by the human interferon-induced tetratricopeptide repeat protein IFIT5. PNAS 111: 12025-30 (2014).
Upton HE, Hong K, Collins K. Direct single-stranded DNA binding by Teb1 mediates the recruitment of Tetrahymena telomerase to telomeres. MCB 34: 4200-12 (2014).
Wu RA, Collins K. Human telomerase specialization for repeat synthesis by unique handling of primer-template duplex. EMBO J. 8: 921-35 (2014)
Collins K, Nilsen TW. Enzyme engineering through evolution: Thermostable recombinant group II intron reverse transcriptases provide new tools for RNA research and biotechnology. RNA 19: 1017-18 (2013).
Hong K, Upton H, Miracco EJ, Jiang J, Zhou ZH, Feigon J, Collins K. Tetrahymena telomerase holoenzyme assembly, activation, and inhibition by domains of the p50 central hub. MCB 33: 3962-71 (2013).
Jiang J, Miracco EJ, Hong K, Eckert B, Chan H, Cash DD, Min B, Zhou ZH*, Collins K, Feigon J. The architecture of Tetrahymena telomerase holoenzyme. Nature 496: 187-192 (2013).
Photo credit: Mark Hanson of Mark Joseph Studios.
Last Updated 2015-09-18