Biomedical Research Education & Training
Faculty Member

Friedman, Katherine L., Ph.D.
Associate Professor of Biological Sciences

Lab Url: N/A

Phone Number: (615) 322-5143

Email Address: katherine.friedman@vanderbilt.edu

Friedman, Katherine's picture
Academic history
BA, Carleton College, Northfield MN
Ph.D., University of Washington, Seattle WA
postdoctoral training, University of Colorado, Boulder CO

Office Address   Mailing Address

2-417 Stevenson Center

Station B Box 351634 37235-1634


Research Keywords
Cancer, Cell cycle, Chromosome, DNA synthesis, Genetics, Yeast, Telomerase, DNA repair

Research Specialty
Maintenance of chromosome ends by telomerase in Saccharomyces cerevisiae.


Research Description
The ends of chromosomes (telomeres) constitute a tiny fraction of DNA in a cell, but play a central role in genome stability and cellular lifespan. Processing of the leading strand results in chromosome shortening following conventional replication. A ribonucleoprotein enzyme, telomerase, replenishes these terminal sequences. Since the catalytic subunit of telomerase is not expressed in most human somatic cells, human chromosomes lose telomere sequence upon successive cell divisions, a process that limits proliferative capacity. DNA loss is reversed in the vast majority of cancers by reactivation of telomerase, allowing cells to far exceed their normal life expectancy. Since inhibition of telomerase triggers apoptosis or senescence of some tumor cell lines, telomerase is a promising target of anti-cancer therapy. Genetic experiments initiated two decades ago established the yeast Saccharomyces cerevisiae as a key model system for studies of telomerase. Furthermore, conservation of several telomerase components between yeast and human suggests that many aspects of yeast telomere biology have correlates in human cells. The ease with which the cell cycle can be manipulated and the vast array of genetic approaches make yeast an ideal system in which to study mechanisms and consequences of telomerase regulation at the cellular level, many of which have relevance for human cells. Our interest is the assembly and regulation of telomerase in S. cerevisiae both at normal chromosome ends and at sites of de novo telomere formation following DNA damage.

Yeast telomerase contains an RNA that provides the template for addition of DNA to chromosome ends, a catalytic protein subunit (Est2p), and other essential protein components (Est1p and Est3p). Telomerase activity is tightly regulated in the cell cycle, occurring only in late S phase. We have shown that part of this regulation occurs through the modulated stability of Est1 protein. Est1p is degraded by the proteasome during G1 phase, precluding telomerase assembly. Inhibiting Est1p degradation allows Est1p to associate with the catalytic core of the telomerase complex and simultaneously recruits Est3p. Our current work is directed toward understanding the regulation of Est1p degradation, determining the mechanism through which Est1p recruits Est3p to the telomerase complex, and examining the role of Est3p in telomerase activation.

Recently, we have begun to examine the phenomenon of de novo telomere formation -- the addition of a new telomere to an internal chromosome site. While de novo telomere addition is normally repressed, it may serve to prevent chromosome loss in the face of irreparable damage. Our study utilizes a "hotspot" for de novo telomere addition on yeast chromosome 5. This ~80 bp region contains TG-rich sequences with similarity to yeast telomeric repeats. We find that function of the Rap1/Rif1/Rif2 complex is required for most de novo telomere addition within and flanking the hotspot. While this complex normally associates with telomeres to negatively regulate telomere length, Rap1/Rif1/Rif2 appears to stimulate telomere addition at ends with little or no telomeric sequence. Mutation of a Rap1p binding site at the centromere-proximal end of the hotspot abolishes telomere addition. Furthermore, chromatin-immunoprecipitation experiments demonstrate that Rap1p associates with hotspot DNA, but only after a chromosome break is induced near the hotspot. Future experiments will examine the mechanism of Rap1p action and address whether other hotspots for telomere addition exist within the yeast genome.

We are also working collaboratively with Dr. Jay Turner at Vanderbilt University to address the relationship between health disparities among racial and economic groups and the levels of stress encountered by these groups. My laboratory's role is to examine telomere length and telomerase activity in study participants as one measure of biological aging.




Publications
Bairley, RC, Guillaume, G, Vega, LR, Friedman, KL. A mutation in the catalytic subunit of yeast telomerase alters primer-template alignment while promoting processivity and protein-DNA binding. J Cell Sci, 124(Pt 24), 4241-52, 2011

Friedman, KL. Telomerase reverse transcriptase and Wnt signaling. Mol Cell Biol, 31(12), 2366-8, 2011

Talley, JM, Dezwaan, DC, Maness, LD, Freeman, BC, Friedman, KL. Stimulation of yeast telomerase activity by the Ever Shorter Telomeres 3 (Est3) subunit is dependent on direct interaction with the catalytic protein Est2. J Biol Chem(286), 26431-26439, 2011

Osterhage, JL, Friedman, KL. Chromosome end maintenance by telomerase. J Biol Chem, 2009 PMCID:2713563

Ji, H, Adkins, CJ, Cartwright, BR, Friedman, KL. Yeast Est2p affects telomere length by influencing association of Rap1p with telomeric chromatin. Mol Cell Biol, 28(7), 2380-2390, 2008 PMCID:2268414

Osterhage, JL, Talley, JM, Friedman, KL. Proteasome-dependent degradation of Est1p regulates the cell cycle-restricted assembly of telomerase in Saccharomyces cerevisiae. Nat Struct Mol Biol, 13(8), 720-8, 2006

Ji, H, Platts, MH, Dharamsi, LM, Friedman, KL. Regulation of telomere length by an N-terminal region of the yeast telomerase reverse transcriptase. Mol Cell Biol, 25(20), 9103-14, 2005 PMCID:1265764

Friedman, KL, Heit, JJ, Long, DM, Cech, TR. N-terminal domain of yeast telomerase reverse transcriptase: recruitment of Est3p to the telomerase complex. Mol Biol Cell, 14(1), 1-13, 2003 PMCID:140223

Friedman, KL, Cech, TR. Essential functions of amino-terminal domains in the yeast telomerase catalytic subunit revealed by selection for viable mutants. Genes Dev, 13(21), 2863-74, 1999 PMCID:317136


Postdoctoral Position Available
No

Postdoctoral Position Details
N/A

Updated Date
08/29/2012