The long-term goal of this proposal is to understand, in detail, the molecular mechanisms of telomere length homeostasis through comprehensive biochemical, structural and functional characterizations of the telomeric shelterin complex and its interaction with telomerase. Telomeres ensure genome integrity by facilitating chromosome end replication through telomerase and protect the chromosome ends from DNA repair and degradation activities. Mutations in telomerase subunits or shelterin components have been linked to premature aging and cancer. Shelterin complex and shelterin-telomerase interactions play essential roles in regulating synthesis of telomeric DNA repeats and defining telomere lengths that support or restrict cell proliferation. We will exploit the genetically amendable fission yeast model system and employ a combination of biochemical, high-resolution structural and genetic tools to achieve the following specific aims: 1. Elucidate the biochemical and structural basis of shelterin assembly and its role in telomere length control; 2. Determine the mechanistic basis for telomere switching from the telomerase non-extendible to extendible state; 3. Determine how the activation of non-extendible telomeric state is coupled to telomerase recruitment. Accomplishment of the proposed aims will provide new and significant mechanistic insights into the structure-function relationship and the dynamics of the shelterin complex, and set up the foundation for the development of new therapeutic approaches against diseases caused by telomere dysfunction, such as premature aging.

Public Health Relevance

Telomeres are closely involved in stem cell differentiation and cancer cell proliferation. The results of this study will lead to new mechanistic principles of telomere length regulation and chromosome end protection. Therefore, valuable targets for mechanism- driven design of anti-aging and cancer therapeutics may be identified through this research.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM098943-10
Application #
9983744
Study Section
Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
Program Officer
Gaillard, Shawn R
Project Start
2012-05-01
Project End
2021-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
10
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92617
Kim, Jin-Kwang; Liu, Jinqiang; Hu, Xichan et al. (2017) Structural Basis for Shelterin Bridge Assembly. Mol Cell 68:698-714.e5
Scott, Harry; Kim, Jin-Kwang; Yu, Clinton et al. (2017) Spatial Organization and Molecular Interactions of the Schizosaccharomyces pombe Ccq1-Tpz1-Poz1 Shelterin Complex. J Mol Biol 429:2863-2872
Hu, Xichan; Liu, Jinqiang; Jun, Hyun-Ik et al. (2016) Multi-step coordination of telomerase recruitment in fission yeast through two coupled telomere-telomerase interfaces. Elife 5:
Wang, Jiyong; Cohen, Allison L; Letian, Anudari et al. (2016) The proper connection between shelterin components is required for telomeric heterochromatin assembly. Genes Dev 30:827-39
Liu, Jinqiang; Yu, Clinton; Hu, Xichan et al. (2015) Dissecting Fission Yeast Shelterin Interactions via MICro-MS Links Disruption of Shelterin Bridge to Tumorigenesis. Cell Rep 12:2169-80
Jun, Hyun-Ik; Liu, Jinqiang; Jeong, Heetae et al. (2013) Tpz1 controls a telomerase-nonextendible telomeric state and coordinates switching to an extendible state via Ccq1. Genes Dev 27:1917-31
Tadeo, Xavier; Wang, Jiyong; Kallgren, Scott P et al. (2013) Elimination of shelterin components bypasses RNAi for pericentric heterochromatin assembly. Genes Dev 27:2489-99