Home Faculty and Research Faculty by Name Kathleen Collins

Kathleen Collins

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

Lab Homepage: http://mcb.berkeley.edu/labs/collins/

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Research Interests

The laboratory studies ribonucleoproteins including the eukaryotic reverse transcriptase telomerase. 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 cycle of genome replication. Cells that do not activate enough telomerase, including most human cells, lose telomeric repeats with every cell division. When telomeric repeat number reaches a critical minimum, short telomeres signal for cell senescence or death. Cancer cells escape this proliferation barrier by activating telomerase. We study telomerase both in vitro, to understand the structural and biochemical principles of this RNA-protein enzyme, and in vivo, to define the complex cellular regulation of telomerase-telomere interaction. We are also investigating the principles of RNA and protein coordination in biological pathways of RNA silencing. Questions of particular interest include how an RNA-dependent RNA polymerase selects specific transcripts as aberrant, in order to target the corresponding loci for silencing, and how the numerous distinct RNA silencing effector RNP complexes are specialized and coordinated in function.

Current Projects

Novel types of protein-nucleic acid interaction establish unique features of the telomerase catalytic cycle. 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 breaks. Both of these specificities are partially recapitulated with recombinant enzyme and are likely to be enhanced by yet uncharacterized other factors. We employ many techniques to study protein, RNA and DNA interactions and to identify new telomerase regulatory proteins using the ciliate Tetrahymena and human cells as major model systems. Because the principles governing co-folding of protein and RNA in vivo remain largely unknown, we are investigating cellular pathways of RNP biogenesis.

RNA-dependent RNA polymerases copy RNA templates to produce yet more RNA, contrary to the central dogma. Although viral RdRPs have clear roles in viral genome replication, the biological significance of eukaryotic RdRP enzymes is just beginning to be investigated. With Tetrahymena as a highly favorable model system, we are using biochemical and genetic methods to dissect how an essential eukaryotic RdRP accomplishes its specificity of aberrant transcript recognition. We are also interested in understanding how different RNA transcripts are recognized as substrates for RNA silencing machinery, how these transcripts are assembled into distinct silencing effector RNP complexes for alternative functional outcomes.

Selected Publications

Lee, S.R. and Collins, K. (2007) Physical and functional coupling of RNA-dependent RNA polymerase and Dicer in the biogenesis of endogenous siRNAs. Nature Structural & Molecular Biology 14: 604-610.

Stone, M.S., Mihalusova, M., O’Connor, C.M., Prathapam, R., Collins, K. and Zhuang, X. (2007) Stepwise protein-mediated RNA folding directs assembly of telomerase ribonucleoprotein. Nature 446: 458-461.

Witkin, K.L., Prathapam, R., and Collins, K. (2007) Positive and negative regulation of Tetrahymena telomerase holoenzyme. Molecular & Cellular Biology 27: 2074-2083.

Hogg, J.R. and Collins, K. (2007) RNA-based affinity purification reveals 7SK RNPs with distinct composition and regulation. RNA 13: 868-880. 

Wong, J.M.Y. and Collins, K. (2006) Telomerase RNA deficiency limits telomere length maintenance in X-linked dyskeratosis congenita. Genes & Development 20: 2848-2458.

Collins, K. (2006) The biogenesis and regulation of telomerase holoenzymes. Nature Reviews Molecular and Cell Biology 6: 484-494.

Fu, D. and Collins, K. (2006) Human telomerase and Cajal body ribonucleoproteins share a unique specificity of Sm protein association.  Genes & Development 20: 531-536. 

O’Connor, C.M. and Collins, K. (2006) A novel RNA binding domain in Tetrahymena telomerase p65 initiates hierarchical assembly of telomerase holoenzyme. Molecular & Cellular Biology 26: 2029-2036.

Lee, S.R. and Collins, K. (2006) Two classes of endogenous small RNAs in Tetrahymena thermophila. Genes & Development 20: 28-33.

Cunningham, D. and Collins, K. (2005) Biological and biochemical functions of RNA in the Tetrahymena telomerase holoenzyme. Molecular & Cellular Biology 25: 4442-4454.  

Prathapam, R., Witkin, K. L., O’Connor, C. M. and Collins, K. (2005) A telomerase holoenzyme protein enhances telomerase RNA assembly with telomerase reverse transcriptase. Nature Structural & Molecular Biology 12: 252-257.

Witkin, K. L. and Collins, K. (2004) Holoenzyme proteins required for the physiological assembly and activity of telomerase. Genes & Development 18: 1107-1118.

Last Updated 2007-07-30