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Telomere repeat binding factors and diagnostic and therapeutic use thereof
| Details |
Inventors: DeLange, Titia; Broccoli, Dominique; Smogorzenska, Agata;
Assignee: The Rockfeller University (New York, NY)
Primary Examiner: Campbell; Eggerton A.
Assistant Examiner:
Attorney, Agent or Firm: Klauber & Jackson
The present invention relates to a novel nucleotide sequence encoding a telomeric protein which binds a repeat region of telomeric sequences, and to the protein encoded thereby. Also included within the invention are expression vectors for the production of the telomeric protein and host cells transformed with the nucleotide sequence. In addition, antibodies, probes and antagonists specific for the telomeric protein are contemplated. Methods of identifying antagonists of the telomeric protein, diagnostic methods of identifying the telomeric protein in a sample, and therapeutic uses of the telomeric protein, particularly in the treatment of aging and cancer, are also contemplated. |
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DETAILED DESCRIPTION The present invention provides vertebrate telomeric binding factors (TRFs) that bind to the TTAGGG repeat sequences of telomeres.
Such TRFs comprise two key domains: a dimerization domain, and a Myb domain.
In addition, at least some TRFs, e.
g.
mammalian TRF1 and TRF2 contain a third domain, a polar N-terminal domain.
In specific examples, the TRF nucleotide sequence is isolated from human, murine, or avian sources.
The present invention includes these nucleic acids, the TRFs they encode, the individual domains of the encoded TRFs, and the nucleic acids that encode these individual domains.
In one particular embodiment of the present invention the TRF has the following characteristics: a) it binds to telomere repeat sequences, in particular, TTAGGG repeats; b) the DNA binding activity in a purified form requires the presence of another factor such as casein; and c) it exhibits substantial sequence homology to Myb type DNA binding domains.
The present invention includes a nucleic acid or a degenerate variant thereof, which encodes a TRF of the present invention; preferably a recombinant DNA molecule or cloned gene.
For example a recombinant DNA molecule or cloned gene, encodes a TRF such a TRF1 which has a nucleotide sequence of (or complementary to) SEQ ID NO:11 (shown in FIGS.
2A-2B), or SEQ ID NO:22.
These nucleotide sequences encode a TRF having an amino acid sequence of SEQ ID NO:12 or 23 respectively which are also part of the present invention.
A nucleotide sequence of a TRF1 having a nucleotide sequence of SEQ ID NO:24 is also part of the present invention.
The present invention also provides an isolated nucleic acid encoding a vertebrate telomere repeat binding factor (TRF) which is a TRF2 having an amino acid sequence substantially homologous to that of SEQ ID NO:27, and comprising the following characteristics: a basic N-terminal domain; a dimerization domain; and a Myb domain.
In one such embodiment when the basic N-terminal domain is removed the TRF detectably binds to the telomere repeat sequence (TTAGGG)
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