Telomere dysfunction is a well-documented contributing factor to diseases such as cancer. Our proposed work should identify new targets and pathways and provide mechanistic details of their function, thereby facilitating in our identifying novel targets for therapies, gaining new insight into the pathways and signals for disease initiation, and shedding light on new and more effective treatment options. We hypothesize that distinct and uncharacterized classes of signaling and regulatory proteins bind directly to core telomeric proteins and modulate telomere homeostasis. Our long-term goal is to elucidate the mechanisms by which telomeric proteins and their associated factors regulate various signaling pathways at the telomeres. The goal of this project is to systematically identify novel regulators recruited to the telomeres by telomeric proteins such as TRF2, and to study how these targets may participate in telomere regulation.
The specific aims of the proposal are:
Specific Aim 1 : To systematically identify new telomere regulators and signaling networks. Genome-wide approaches will be employed to identify new cellular targets of TRF2, and generate high-resolution maps of TRF2-centric signaling networks. Secondary screens are proposed to confirm and prioritize the targets identified.
Specific Aim 2 : To determine the function of the newly identified regulators.
This aim will focus on new TRF2 targets PNUTS and ubiquitin E3 ligases, in their regulation of TRF2 function and telomere maintenance, and possible roles in extra-telomeric activities.

Public Health Relevance

In this proposal, we seek to understand the signaling mechanisms by which protein networks centering around the telomere binding protein TRF2 regulate telomere maintenance in human cells. The proposed work should provide insight into the regulation of telomere protection and genome integrity. Furthermore, valuable targets for early detection and mechanism-driven therapeutic design of cancer and aging-related diseases may be identified through this project.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM095599-03
Application #
8512741
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Carter, Anthony D
Project Start
2011-08-01
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$285,433
Indirect Cost
$103,048
Name
Baylor College of Medicine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Zhang, Youwei; Wu, Yangxiu; Mao, Pingsu et al. (2016) Cold-inducible RNA-binding protein CIRP/hnRNP A18 regulates telomerase activity in a temperature-dependent manner. Nucleic Acids Res 44:761-75
He, Quanyuan; Kim, Hyeung; Huang, Rui et al. (2015) The Daxx/Atrx Complex Protects Tandem Repetitive Elements during DNA Hypomethylation by Promoting H3K9 Trimethylation. Cell Stem Cell 17:273-86
Tang, Mengfan; Li, Yujing; Zhang, Yi et al. (2015) Disease mutant analysis identifies a new function of DAXX in telomerase regulation and telomere maintenance. J Cell Sci 128:331-41
Luo, Zhenhua; Feng, Xuyang; Wang, Haoli et al. (2015) Mir-23a induces telomere dysfunction and cellular senescence by inhibiting TRF2 expression. Aging Cell 14:391-9
Tang, Mengfan; Li, Yujing; Zhang, Xiya et al. (2014) Structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) promotes non-homologous end joining and inhibits homologous recombination repair upon DNA damage. J Biol Chem 289:34024-32
Zhou, Ge; Wang, Jiping; Zhao, Mei et al. (2014) Gain-of-function mutant p53 promotes cell growth and cancer cell metabolism via inhibition of AMPK activation. Mol Cell 54:960-74
Liu, Yinyin; Kim, Hyeung; Liang, Jiancong et al. (2014) The death-inducer obliterator 1 (Dido1) gene regulates embryonic stem cell self-renewal. J Biol Chem 289:4778-86
Li, Yujing; Fong, Ka-Wing; Tang, Mengfan et al. (2014) Fam118B, a newly identified component of Cajal bodies, is required for Cajal body formation, snRNP biogenesis and cell viability. J Cell Sci 127:2029-39
Feng, Xuyang; Luo, Zhenhua; Jiang, Shuai et al. (2013) The telomere-associated homeobox-containing protein TAH1/HMBOX1 participates in telomere maintenance in ALT cells. J Cell Sci 126:3982-9
Lu, Weisi; Zhang, Yi; Liu, Dan et al. (2013) Telomeres-structure, function, and regulation. Exp Cell Res 319:133-41

Showing the most recent 10 out of 20 publications