The aim of the research in this proposal is to understand the mechanisms of telomere function in eukaryotes. Telomeres are essential chromosomal elements which stabilize the ends of linear nuclear chromosomes and allow their complete replication. Much of the proposed work emphasizes the ciliated protozoans Tetrahymena and Euplotes, which, because of specific aspects of their biology, afford advantageous experimental systems for study of telomere, function. Telomere structure is highly conserved throughout eukaryotes, and findings made in one system are likely to be relevant to general questions of telomere function.
Specific aims are to 1) determine the function of the essential RNA of a novel ribonucleoprotein enzyme, telomerase, that synthesizes the G-rich strand of the simple repeated sequences that form the essential cis-acting components of telomeres, 2) determine what structural features of telomeric DNA are required for recognition by telomerase, and investigate the mechanism of de novo telomere formation that occurs in ciliate macronuclear differentiation and chromosome healing, 3) investigate the enzymes responsible for synthesis of the complementary C-rich telomeric strand. 4) study the mechanism of genomic rearrangements in ciliate development, using an in vitro reaction system we have developed.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
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University of California San Francisco
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Jay, Kyle A; Smith, Dana L; Blackburn, Elizabeth H (2016) Early Loss of Telomerase Action in Yeast Creates a Dependence on the DNA Damage Response Adaptor Proteins. Mol Cell Biol 36:1908-19
Xie, Zhengwei; Jay, Kyle A; Smith, Dana L et al. (2015) Early telomerase inactivation accelerates aging independently of telomere length. Cell 160:928-939
Blackburn, Elizabeth H; Epel, Elissa S; Lin, Jue (2015) Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection. Science 350:1193-8
Makovets, Svetlana; Blackburn, Elizabeth H (2009) DNA damage signalling prevents deleterious telomere addition at DNA breaks. Nat Cell Biol 11:1383-6
Seidel, Jeffrey J; Anderson, Carol M; Blackburn, Elizabeth H (2008) A novel Tel1/ATM N-terminal motif, TAN, is essential for telomere length maintenance and a DNA damage response. Mol Cell Biol 28:5736-46
Makovets, Svetlana; Williams, Tanya L; Blackburn, Elizabeth H (2008) The telotype defines the telomere state in Saccharomyces cerevisiae and is inherited as a dominant non-Mendelian characteristic in cells lacking telomerase. Genetics 178:245-57
Hsu, Min; McEachern, Michael J; Dandjinou, Alain T et al. (2007) Telomerase core components protect Candida telomeres from aberrant overhang accumulation. Proc Natl Acad Sci U S A 104:11682-7
Epel, Elissa S; Lin, Jue; Wilhelm, Frank H et al. (2006) Cell aging in relation to stress arousal and cardiovascular disease risk factors. Psychoneuroendocrinology 31:277-87
Blackburn, Elizabeth H (2005) Telomeres and telomerase: their mechanisms of action and the effects of altering their functions. FEBS Lett 579:859-62
Makovets, Svetlana; Herskowitz, Ira; Blackburn, Elizabeth H (2004) Anatomy and dynamics of DNA replication fork movement in yeast telomeric regions. Mol Cell Biol 24:4019-31

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