Telomeres protect chromosome ends, and telomerase synthesizes and replenishes the telomeric DNA central to the protective DNA-protein complex of the telomere. Budding yeast will be used to investigate essential and conserved processes of telomere maintenance.
Aim 1 focuses on interactions of core telomeric protein components (yeast Rap1 and Rif2) with telomeric DNA, to dissect fundamental mechanisms underlying the dynamics of their associations, which are crucial to telomere function. It was found that telomere/telomerase status is constantly monitored in cells, with loss of telomere maintenance in yeast causing responses at a stage earlier than previously thought. The details of the interactions that affect yeast cell proliferation upon such early telomerase loss will be dissected:
Aim 2 will identify the immediate molecular lesion at telomeres caused by telomerase inactivation, and examine immediate cellular responses to telomerase shut-off. Two growth-controlling pathways were identified that cross-talk with telomere maintenance status: in combination with early telomerase loss, disruption of either DNA damage checkpoint signaling or TOR signaling causes lethality.
Aim 2 B will test models for the requirement of DNA checkpoint proteins Mrc1 and Rad9.
Aim 3 will test models for how TOR signaling pathways and early telomere loss interact. Pursuing the finding that early telomerase loss causes major defects in meiosis, Aim 4 wil test the molecular requirements for telomerase and telomeres for successful meiosis. Finally, given the intersection of telomere status with TOR signaling, which affects cell aging, and other recent evidence, Aim 5 will examine the role of telomere deprotection in the budding aging of yeast mother cells. Understanding the mechanisms by which telomere maintenance status is sensed and integrated with pathways that control cell proliferation is a core goal of this proposal. This project is thus highly relevant to how telomere status integrates with other cellular processes, such as nutritional signaling, that regulate human aging, morbidity and mortality.

Public Health Relevance

Telomere status is clearly related to the onset and outcome of multiple human aging-related diseases and conditions. Knowing how telomere dysfunction/deprotection influences aging and cancer processes is thus important for efforts to understand both growing and aging human cells. The findings will help design appropriate therapeutics in disease and beneficially impact human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM026259-35
Application #
8294577
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Carter, Anthony D
Project Start
1990-07-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
35
Fiscal Year
2012
Total Cost
$611,776
Indirect Cost
$207,935
Name
University of California San Francisco
Department
Biochemistry
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Makovets, Svetlana; Blackburn, Elizabeth H (2009) DNA damage signalling prevents deleterious telomere addition at DNA breaks. Nat Cell Biol 11:1383-6
Li, Shang; Makovets, Svetlana; Matsuguchi, Tetsuya et al. (2009) Cdk1-dependent phosphorylation of Cdc13 coordinates telomere elongation during cell-cycle progression. Cell 136:50-61
Anderson, Carol M; Blackburn, Elizabeth H (2008) Mec1 function in the DNA damage response does not require its interaction with Tel2. Cell Cycle 7:3695-8
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
Chan, Simon R W L; Blackburn, Elizabeth H (2004) Telomeres and telomerase. Philos Trans R Soc Lond B Biol Sci 359:109-21

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