Method of controlling telomere length

• US 20060142218A1
• Filed: 02/14/2001
• Published: 06/29/2006
• Est. Priority Date: 02/18/2000
• Status: Abandoned Application

• Current Assignee: Japan Science And Technology Corpration, Riken
• Original Assignee: Japan Science And Technology Corpration, Riken
• Inventors: Shibata, Takehiko, Ohta, Kunihiro
• Application Number:
  US10/204,067
• Publication Number:
  US 20060142218A1
• Time in Patent Office: Days
• US Class Current: 514/44.R
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/395 from Saccharomyces
• CPC Class Codes: C12N 9/22 Ribonucleases RNAses, DNAses catalytic nucleic acids C12N15/113

Abstract

A method of controlling telomere length wherein the method comprises introducing into a cell a DNA encoding Mre11 protein or a DNA encoding a protein comprising Mre11 protein wherein a part of the nuclease domain, the C-terminal domain or the whole thereof is modified or deleted.

Claims

1. A method of controlling telomere length wherein the method comprises modifying physiological activity of endogenous Mre11 protein in a eukaryotic cell.

2. The method of controlling telomere length according to claim 1, wherein the modification of physiological activity of the endogenous Mre11 protein is carried out by introducing into a cell a DNA encoding foreign Mre11 protein or a DNA encoding a protein wherein the nuclease domain or the C-terminal domain of the foreign Mre11 protein is modified, in a state such that the DNA can be expressed.

3. The method of controlling telomere length according to claim 2, wherein the foreign Mre11 protein is the following protein (a) or (b):

(a) a protein comprising an amino acid sequence represented by SEQ ID NO;

2 or 4;

or

(b) a protein comprising an amino acid sequence which is the amino acid sequence represented by SEQ ID NO;

2 or 4 from, in, or to which one or more amino acids are deleted, substituted or added, and having physiological activity of Mre11 protein.

4. The method of controlling telomere length according to claim 2, wherein the DNA encoding the foreign Mre11 protein is the following DNA (c) or (d):

(c) a DNA comprising a nucleotide sequence represented by SEQ ID NO;

1 or 3;

or

(d) a DNA which can hybridize with the DNA of (c) under a stringent condition and encodes a protein having physiological activity of Mre11 protein.

5. The method of controlling telomere length according to claim 2, wherein the protein having the modified nuclease domain of the foreign Mre11 protein is the following protein (e) or (f):

(e) a protein comprising an amino acid sequence represented by SEQ ID NO;

6;

or

f) a protein comprising an amino acid sequence which is the amino acid sequence represented by SEQ ID NO;

6 from, in, or to which one or more amino acids are deleted, substituted or added, and having physiological activity (except nuclease activity) of Mre11 protein.

6. The method of controlling telomere length according to claim 2, wherein the DNA encoding the protein having the modified nuclease domain of the foreign Mre11 protein is the following DNA (g) or (h):

(g) a DNA comprising a nucleotide sequence represented SEQ ID NO;

5;

or

(h) a DNA which can hybridize with the DNA of (g) under a stringent condition and encodes a protein having physiological activity (except nuclease activity) of Mre11 protein.

7. The method of controlling telomere length according to claim 2, wherein the protein having the modified C-terminal domain of the foreign Mre11 protein is the following protein (i) or (j):

(i) a protein comprising an amino acid sequence represented by SEQ ID NO;

8;

or

(j) a protein comprising an amino acid sequence which is the amino acid sequence represented by SEQ ID NO;

8 from, in or to which one or more amino acids are deleted, substituted or added, and having physiological activity (except double-stranded DNA binding activity) of Mre11 protein.

8. The method of controlling telomere length according to claim 2, wherein the DNA encoding the protein having the modified C-terminal domain of the foreign Mre11 protein is the following DNA (k) or (1):

(k) a DNA comprising a nucleotide sequence represented by SEQ ID NO;

7;

or

(l) a DNA which can hybridize with the DNA of (k) and encodes a protein having physiological activity (except double-stranded DNA binding activity) of Mre11 protein.

9. An agent for controlling telomere length comprising as an active component a substance which modifies physiological activity of endogenous Mre11 protein in a eukaryotic cell.

10. The agent for controlling telomere length according to claim 9, wherein the substance is a DNA construct which comprises a DNA encoding a foreign Mre11 protein or a DNA encoding a protein wherein the nuclease domain or the C-terminal domain of the Mre11 protein is modified in a state such that the DNA can be expressed.

11. The agent for controlling telomere length according to claim 10, wherein the foreign Mre11 protein is the following protein (a) or (b):

(a) a protein comprising an amino acid sequence represented by SEQ ID NO;

2 or 4;

or

(b) a protein comprising an amino acid sequence which is the amino acid sequence represented by SEQ ID NO;

2 or 4 from, in, or to which one or more amino acids are deleted, substituted or added, and having physiological activity of Mre11 protein.

12. The agent for controlling telomere length according to claim 10, wherein the DNA encoding the foreign Mre11 protein is the following DNA (c) or (d):

(c) a DNA comprising a nucleotide sequence represented by SEQ ID NO;

1 or 3;

or

(d) a DNA which can hybridize with the DNA of (c) under a stringent condition and encodes a protein having physiological activity of Mre11 protein.

13. The agent for controlling telomere length according to claim 10, wherein the protein having the modified nuclease domain of the foreign Mre11 protein is the following protein (e) or (f):

(e) a protein comprising an amino acid sequence represented by SEQ ID NO;

6;

or

(f) a protein comprising an amino acid sequence which is the amino acid sequence represented by SEQ ID NO;

6 from, in, or to. which one or more amino acids are deleted, substituted or added, and having physiological activity (except nuclease activity) of Mre11 protein.

14. The agent for controlling telomere length according to claim 10, wherein the DNA encoding the protein having the modified nuclease domain of the foreign Mre11 protein is the following DNA (g) or (h):

(g) a DNA comprising a nucleotide sequence represented SEQ ID NO;

5;

or

(h) a DNA which can hybridize with the DNA of (g) under a stringent condition and encodes a protein having physiological activity (except nuclease activity) of Mre11 protein.

15. The agent for controlling telomere length according to claim 10, wherein the protein having the modified C-terminal domain of the foreign Mre11 protein is the following protein (i) or ():

(i) a protein comprising an amino acid sequence represented by SEQ ID NO;

8;

or

(j) a protein comprising an amino acid sequence which is the amino acid sequence represented by SEQ ID NO;

8 from, in or to which one or more amino acids are deleted, substituted or added, and having physiological activity (except double-stranded DNA binding activity) of Mre11 protein.

16. The agent for controlling telomere length according to claim 10, wherein the DNA encoding the protein having the modified C-terminal domain of the foreign Mre11 protein is the following DNA (k) or (1):

(k) a DNA comprising a nucleotide sequence represented by SEQ ID NO;

7;

or

(l) a DNA which can hybridize with the DNA of (g) and encodes a protein having physiological activity (except double-stranded DNA binding activity) of Mre11 protein.

17. A gene therapeutic agent for a telomere length-associated disease comprising as an active agent a substance which modifies physiological activity of endogenous Mre11 protein in a eukaryotic cell.

18. The gene therapeutic agent according to claim 17, wherein the substance is a DNA construct which comprises a DNA encoding foreign Mre11 protein or a DNA encoding a protein wherein the nuclease domain or the C-terminal domain of the Mre11 protein is modified, in a state such that the DNA can be expressed.

19. The gene therapeutic agent according to claim 17, wherein the telomere length-associated disease is a malignant tumor or a cell senescent disease.

20. The gene therapeutic agent according to claim 19, wherein the malignant tumor is at least one selected from the group consisting of melanoma, hepatoma breast cancer, gastric cancer, and brain tumor.

21. The gene therapeutic agent according to claim 18, wherein the foreign Mre11 protein is the following protein (a) or (b):

(a) a protein comprising an amino acid sequence represented by SEQ ID NO;

2 or 4;

or

(b) a protein comprising an amino acid sequence which is the amino acid sequence represented by SEQ ID NO;

2 or 4 from, in, or to which one or more amino acids are deleted, substituted or added, and having physiological activity of Mre11 protein.

22. The gene therapeutic agent according to claim 18, wherein the DNA encoding the foreign Mre11 protein is the following DNA (c) or (d):

(c) a DNA comprising a nucleotide sequence represented by SEQ ID NO;

1 or 3;

or

(d) a DNA which can hybridize with the DNA of (c) under a stringent condition and encodes a protein having physiological activity of Mre11 protein.

23. The gene therapeutic agent according to claim 18, wherein the protein having the modified nuclease domain of the foreign Mre11 protein is the following protein (e) or (f):

(e) a protein comprising an amino acid sequence represented by SEQ ID NO;

6;

or

(f) a protein comprising an amino acid sequence which is the amino acid sequence represented by SEQ ID NO;

6 from, in, or to which one or more amino acids are deleted, substituted or added, and having physiological activity (except nuclease activity) of Mre11 protein.

24. The gene therapeutic agent according to claim 18, wherein the DNA encoding the protein having the modified nuclease domain of the foreign Mre11 protein is the following DNA (g) or (h):

(g) a DNA comprising a nucleotide sequence represented SEQ ID NO;

5;

or

(h) a DNA which can hybridize with the DNA of (g) under a stringent condition and encodes a protein having physiological activity (except nuclease activity) of Mre11 protein.

25. The gene therapeutic agent according to claim 18, wherein the protein having the modified C-terminal domain of the foreign Mre11 protein is the following protein (i) or ():

(i) a protein comprising an amino acid sequence represented by SEQ ID NO;

8;

or

(j) a protein comprising an amino acid sequence which is the amino acid sequence represented by SEQ ID NO;

8 from, in or to which one or more amino acids are deleted, substituted or added, and having physiological activity (except double-stranded DNA binding activity) of Mre11 protein.

26. The gene therapeutic agent according to claim 18, wherein the DNA encoding the protein having the modified C-terminal domain of the foreign Mre11 protein is the following DNA (k) or (1):

(k) a DNA comprising a nucleotide sequence represented by SEQ ID NO;

7;

or

(l) a DNA which can hybridize with the DNA of (g) and encodes a protein having physiological activity (except double-stranded DNA binding activity) of Mre11 protein.