Faculty Research Page
Professor of Biochemistry, Biophysics and Structural Biology*
*And Affiliate, Division of Cell and Developmental Biology
Collins lab interests focus on RNAs, RNPs and non-canonical RNA-template-dependent polymerases.
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 ranging from single-molecule imaging to genome engineering, within the lab and through collaborations. Through collaborations we are extending our holoenzyme structure determination by electron microscopy to reach atomic resolution.
New functions for non-coding RNA
We have been applying our insights from studies of telomerase RNA to more general investigations of non-coding (nc) RNA biogenesis and function. In human cells we have discovered new ncRNA processing pathways and ncRNA functions in stress response and innate immunity. In Tetrahymena we are exploiting the evolutionary specialization of individual members of a large Piwi protein family to resolve Piwi protein functions in heterochromatin formation from other roles. We continue to discover new mechanisms by which nuclear-localized Piwi proteins influence RNA metabolism, gene expression and trans-generational epigenetic inheritance. Also we are particularly interested in eukaryotic RNA-dependent RNA polymerases and the specificities of RNA template selection and duplex RNA processing in vitro and in vivo.
Sexton AN, Regalado SG, Lai CS, Cost GJ, O'Neil CM, Urnov FD, Gregory PD, Jaenisch R, Collins K*, Hockemeyer D* (*co-corresponding authors). 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* (*co-corresponding authors). 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* (*co-corresponding authors). 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* (*co-corresponding authors). The architecture of Tetrahymena telomerase holoenzyme. Nature 496: 187-192 (2013).
Katibah GE, Lee HJ, Huizar JP, Vogan JM, Alber T, Collins K. tRNA binding, structure, and localization of the human interferon-induced protein IFIT5. Mol. Cell 49: 743-750 (2013).
Couvillion MT, Bounova G, Purdom E, Speed TP, Collins K. A Tetrahymena Piwi bound to mature tRNA 3' fragments activates the exonuclease Xrn2 for RNA processing in the nucleus. Mol. Cell 48: 509-520 (2012).
Sexton AN, Youmans DT, Collins K. Specificity requirements for human telomere protein interaction with telomerase holoenzyme. JBC (2012).
Egan ED, Collins K. An enhanced H/ACA RNP assembly mechanism for human telomerase RNA. MCB 32: 2428-39 (2012).
Photo credit: Mark Hanson of Mark Joseph Studios.
Last Updated 2015-08-16