Telomeres protect chromosome ends and allow for chromosome length maintenance. Telomerase is the enzyme that maintains telomeres by the addition of telomere repeat sequences onto chromosome ends. Inactivating telomerase activity leads to progressive telomere shortening and loss of telomere function. Many human cells do not express telomerase and telomeres shorten throughout their lifespan. For cells with a limited requirement for division, this shortening has no consequence. However, most tumor cells reactivate telomerase to allow for continued growth. Telomerase is thus a target for cancer therapy as inhibition of telomerase should lead to telomere dysfunction and cell death. We are using yeast to dissect the details of the consequences of telomerase inactivation. Short telomeres lead to both an increase in genetic instability and to cell cycle arrest and, in mammalian cells, to apoptosis. In recent work we found that non-reciprocal translocations occur frequently in yeast cells that lack telomerase. Such non reciprocal translocations are frequently found in tumors and may be a major mechanism for loss of heterozygosity. Here we propose experiments designed to determine the molecular events that initiate these translocations. In addition to chromosomal rearrangements, we found that loss of telomere function leads to a cell cycle checkpoint arrest in yeast. This arrest requires components of the DNA damage response pathway. In the next several years we will investigate this response pathway and determine whether there are mechanisms that specifically recognize telomere dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM043080-15
Application #
6734242
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Carter, Anthony D
Project Start
1989-12-01
Project End
2007-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
15
Fiscal Year
2004
Total Cost
$408,750
Indirect Cost
Name
Johns Hopkins University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Kaizer, Hannah; Connelly, Carla J; Bettridge, Kelsey et al. (2015) Regulation of Telomere Length Requires a Conserved N-Terminal Domain of Rif2 in Saccharomyces cerevisiae. Genetics 201:573-86
Ma, Yunmei; Greider, Carol W (2009) Kinase-independent functions of TEL1 in telomere maintenance. Mol Cell Biol 29:5193-202
Frank, Christopher J; Hyde, Molly; Greider, Carol W (2006) Regulation of telomere elongation by the cyclin-dependent kinase CDK1. Mol Cell 24:423-32
IJpma, Arne S; Greider, Carol W (2003) Short telomeres induce a DNA damage response in Saccharomyces cerevisiae. Mol Biol Cell 14:987-1001
Hackett, Jennifer A; Greider, Carol W (2003) End resection initiates genomic instability in the absence of telomerase. Mol Cell Biol 23:8450-61
Hackett, Jennifer A; Greider, Carol W (2002) Balancing instability: dual roles for telomerase and telomere dysfunction in tumorigenesis. Oncogene 21:619-26
Chen, Q; Ijpma, A; Greider, C W (2001) Two survivor pathways that allow growth in the absence of telomerase are generated by distinct telomere recombination events. Mol Cell Biol 21:1819-27
Mason, D X; Autexier, C; Greider, C W (2001) Tetrahymena proteins p80 and p95 are not core telomerase components. Proc Natl Acad Sci U S A 98:12368-73
Hackett, J A; Feldser, D M; Greider, C W (2001) Telomere dysfunction increases mutation rate and genomic instability. Cell 106:275-86
Kass-Eisler, A; Greider, C W (2000) Recombination in telomere-length maintenance. Trends Biochem Sci 25:200-4

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