Department of Molecular & Cell Biology

Home Faculty and Research Faculty by Name Kathleen Collins

Kathleen Collins

Professor of Biochemistry, Biophysics and Structural Biology*
*And Affiliate, Division of Cell and Developmental Biology

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Research Interests

The eukaryotic ribonucleoprotein reverse transcriptase telomerase adds simple-sequence repeats to chromosome ends by copying a template within its RNA subunit. This telomeric repeat synthesis balances the loss of repeats that occurs with each round of genome replication. Cells that do not activate enough telomerase, including most normal human somatic cells, lose telomeric repeats with every cell division. When telomeric repeat number reaches a critical minimum, short telomeres signal for exit from the cell cycle. Cancer cells escape this proliferation barrier by activating telomerase. We study telomerase both in vitro, to understand the structure and biochemical mechanisms of this unique polymerase, and in vivo, to understand the cellular regulation of telomerase-telomere interaction. We are similarly investigating the eukaryotic RNA-dependent RNA polymerase complexes that select specific transcripts to initiate endogenous pathways of small-RNA-mediated silencing.

Current Projects

Novel modes of protein-nucleic acid interaction confer the unique features of a telomerase catalytic cycle of single-stranded telomeric-repeat synthesis. For example, telomerase must define a precise region of its RNA subunit as the template for reverse transcription. Also, telomerase must recognize authentic chromosome ends as substrates while ignoring random DNA breaks. We study telomerase protein, RNA, and DNA interactions using model enzymes from the ciliate Tetrahymena and human cells. We are also investigating the stepwise cellular pathways of telomerase RNP biogenesis to uncover the principles of protein and RNA co-folding.

Eukaryotic RNA-dependent RNA polymerases create the double-stranded RNA that initiates cellular RNA silencing pathways. With Tetrahymena as a highly favorable model system, we are using molecular, biochemical, and genetic methods to dissect the principles that underlie the critical biological specificity of initial transcript recognition for double-stranded RNA synthesis. We are investigating how different RNA transcripts can be segregated to distinct silencing pathways coupled to the assembly of different effector Piwi-protein RNP complexes.

Selected Publications

Collins K. Single-stranded DNA repeat synthesis by telomerase. Curr. Op. Chem. Biol. in press (2011).

Robart AR, Collins K. Human telomerase domain interactions capture DNA for TEN-domain-dependent processive elongation. Mol. Cell 42: 308-318 (2011).

Blackburn EH, Collins K. "Telomerase: an RNP enzyme synthesizes DNA" in RNA Worlds, JF Atkins, TR Cech and RF Gesteland, Eds. Cold Spring Harbor Laboratory Press (2010).

Robart AR, Collins K. Investigation of human telomerase holoenzyme assembly, activity, and processivity using disease-linked subunit variants. J. Biol. Chem. 285: 4375-4386 (2010).

Egan ED, Collins K. Specificity and stoichiometry of subunit interactions in the human telomerase holoenzyme assembled in vivo. Mol. Cell. Biol. 30: 2775-2786 (2010).

Min B, Collins K. Multiple mechanisms for elongation processivity within the reconstituted Tetrahymena telomerase holoenzyme. J. Biol. Chem. 285:16434-16443 (2010).

Talsky KB, Collins, K. Initiation by a eukaryotic RNA-dependent RNA polymerase requires looping of the template end and is influenced by the template-tailing activity of an associated uridyltransferase. J. Biol. Chem.  285: 27614-27623 (2010).

Couvillion MT, Sachidanandam R, Collins K. A growth-essential Tetrahymena Piwi protein carries tRNA fragment cargo. Genes Dev. 24: 2742-2747 (2010).

 Lee SR, Talsky KB, Collins K. A single RNA-dependent RNA polymerase assembles with mutually exclusive nucleotidyl transferase subunits to direct different pathways of small RNA biogenesis. RNA 15: 1362-1374 (2009).

Couvillion MT, Lee SR, Hogstad B, Malone CD, Tonkin LA, Sachidanandam R, Hannon GJ, Collins K. Sequence, biogenesis, and function of diverse small RNA classes bound to the Piwi-family proteins of Tetrahymena thermophila. Genes Dev. 23: 2016-2032 (2009).

Min B, Collins K. An RPA-related sequence-specific DNA binding subunit of telomerase holoenzyme is required for elongation processivity and telomere maintenance. Mol. Cell 36: 609-619 (2009).

Last Updated 2011-08-08