TRF1 is a mammalian telomere binding protein identified and cloned by Dr. DeLange. The protein clearly resides at telomeres in stained cells. The structure of the protein reveals an acidic N-terminus, a dimerization domain, and a C-terminal myb DNA-binding domain. The mouse and human proteins are related along their lengths. In addition, there is a second telomere binding protein TRF2 which shows strong homology to TRF1 in the DNA-binding domain and weaker homology elsewhere. This protein has also been shown to bind to the telomere repeat sequence and to reside at telomeres in cells. A key observation leading to this proposal is that the length of telomeres in telomerase expressing cells can be influenced by varying the level of TRF1. Increased expression of TRF1 leads to shortening, while expression of a dominant negative construct (dimerization domain) leads to lengthening. These operations do not affect levels of telomerase by in vitro assay. The model for these findings is that the TRF1 at telomeres down regulates telomerase as a homeostatic mechanism to maintain telomere length. This is similar to a model in yeast involving RAP1. In this proposal the aims are: 1 Test a model for the role of TRF1 in telomere length control by tethering the protein using the GAL4 DBD. 2. Determine the contribution of TRF2 to telomere length control. 3. Create TRF1 and TRF2 null mutations in chicken cells. 4. Alter TRF1 levels in telomerase negative cells. 5. Inhibit TRF1 in human T-cells. 6. Knock out TRF1 in the mouse germ line.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA076027-04
Application #
6328990
Study Section
Molecular Biology Study Section (MBY)
Program Officer
Okano, Paul
Project Start
1997-12-15
Project End
2002-03-31
Budget Start
2000-12-08
Budget End
2002-03-31
Support Year
4
Fiscal Year
2001
Total Cost
$265,316
Indirect Cost
Name
Rockefeller University
Department
Anatomy/Cell Biology
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Lovejoy, Courtney A; Li, Wendi; Reisenweber, Steven et al. (2012) Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway. PLoS Genet 8:e1002772
Sfeir, Agnel; de Lange, Titia (2012) Removal of shelterin reveals the telomere end-protection problem. Science 336:593-7
Wu, Peng; Takai, Hiroyuki; de Lange, Titia (2012) Telomeric 3' overhangs derive from resection by Exo1 and Apollo and fill-in by POT1b-associated CST. Cell 150:39-52
Davoli, Teresa; de Lange, Titia (2011) The causes and consequences of polyploidy in normal development and cancer. Annu Rev Cell Dev Biol 27:585-610
Wu, Peng; van Overbeek, Megan; Rooney, Sean et al. (2010) Apollo contributes to G overhang maintenance and protects leading-end telomeres. Mol Cell 39:606-17
de Lange, T (2010) How shelterin solves the telomere end-protection problem. Cold Spring Harb Symp Quant Biol 75:167-77
Takai, Kaori K; Hooper, Sarah; Blackwood, Stephanie et al. (2010) In vivo stoichiometry of shelterin components. J Biol Chem 285:1457-67
Kabir, Shaheen; Sfeir, Agnel; de Lange, Titia (2010) Taking apart Rap1: an adaptor protein with telomeric and non-telomeric functions. Cell Cycle 9:4061-7
Sfeir, Agnel; Kosiyatrakul, Settapong T; Hockemeyer, Dirk et al. (2009) Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication. Cell 138:90-103
de Lange, Titia (2009) How telomeres solve the end-protection problem. Science 326:948-52

Showing the most recent 10 out of 32 publications