Nucleic acid molecules encoding DRT111 and uses thereof

Details Nucleic acid molecules encoding DRT111 and uses thereof Nucleic acid molecules encoding DRT111 and uses thereof

2000-01-20

2004-02-10

Shukla, Ram R. (Department: 1635)

Chemistry: natural resins or derivatives; peptides or proteins;

Proteins, i.e., more than 100 amino acid residues

C435S006120, C435S069100, C435S091100, C435S455000, C530S300000, C536S023100, C536S023500

Reexamination Certificate

active

06689865

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention relates to chemotherapy and DNA repair.
Cancer chemotherapy involves the administration of one or more cytotoxic or cytostatic drugs to a patient. The goal of chemotherapy is to eradicate a substantially clonal population (tumor) of transformed cells from the body of the individual, or to suppress or to attenuate growth of the tumor. Tumors may occur in solid or liquid form, the latter comprising a cell suspension in blood or other body fluid. A secondary goal of chemotherapy is stabilization (clinical management) of the afflicted individual's health status. Although the tumor may initially respond to chemotherapy, in many instances the initial chemotherapeutic treatment regimen becomes less effective or ceases to impede tumor growth. The selection pressure induced by chemotherapy promotes the development of phenotypic changes that allow tumor cells to resist the cytotoxic effects of a chemotherapeutic drug.
Several chemotherapeutic drugs function by preferentially damaging DNA in actively dividing cells. The treated cells stop proliferating because the damaged genomic DNA is unable to support further mitosis. Types of DNA-damaging chemotherapeutic drugs include those that covalently modify bases (e.g., alkylating agents such as cyclophosphamide) and base analogs (e.g., 5-bromouracil). After chronic exposure to these drugs, tumor cells can become resistant to their effects.
One mechanism by which cells resist chemotherapeutic drugs is modulation of DNA repair processes. For an overview, see, Barrett et al. (1998)
Anticancer Drugs
, 9:105-123. The expression or activity of several different enzymes involved in repairing damaged DNA are altered in chemotherapeutic drug-resistant cells. For example, O
6
-alkylguanine-DNA alkyltransferase, a DNA repair enzyme, exhibits higher expression in cells less sensitive to alkylating chemotherapeutic drugs than in cell more sensitive to the drugs. Belanich et al. (1996)
Cancer Res
., 56:783-788. Similarly, DNA polymerase a, DNA polymerase &bgr;, and topoisomerase II are elevated in some tumor cells that are resistant to chemotherapeutic drugs. Friedman et al. (1994)
Cancer Res
., 54:3487-93. In addition to these, many more DNA repair enzymes are aberrantly expressed in some drug-resistant tumor cells, including, for example: AP endonuclease and DNA glycosylases. See, Barrett et al., supra.
SUMMARY OF THE INVENTION
The present invention is based, at least in part, on the discovery of the human gene encoding DRT111. The apparent murine homolog of human DRT111 is expressed at a higher level in a cyclophosphamide-resistant variant of the murine tumor cell line EMT-6 CTX than in the EMT-6 cell line from which EMT-6 CTX tumor cells are derived. The human DRT111 cDNA described below (SEQ ID NO:1) has a 1203 nucleotide open reading frame (nucleotides 145-1348 of SEQ ID NO:1; SEQ ID NO:3) which encodes a 401 amino acid protein (SEQ ID NO:2). The cDNA encoding human DRT111 is 35% identical to the cDNA encoding
Arabidopsis thaliana
DRT111, a gene that encodes a protein thought to be involved in DNA damage repair. DRT111 nucleic acids and polypeptides, as well as molecules which increase or decrease expression or activity of DRT111, are expected to be useful in the diagnosis and treatment of disorders associated with aberrant DNA damage repair (e.g., drug-resistant cancer).
The DRT111 molecules of the present invention are useful as modulating agents in regulating a variety of cellular processes. Accordingly, in one aspect, this invention provides isolated nucleic acid molecules encoding DRT111 proteins or biologically active portions thereof, as well as nucleic acid fragments suitable as primers or hybridization probes for the detection of DRT111-encoding nucleic acids.
The invention features a nucleic acid molecule which is at least 45% (or 55%, 65%, 75%, 85%, 95%, or 98%) identical to the nucleotide sequence shown in SEQ ID NO:1, or SEQ ID NO:3, or the nucleotide sequence of the cDNA insert of the plasmid deposited with ATCC as Accession Number (the “cDNA of ATCC 209937”), or a complement thereof.
The invention features a nucleic acid molecule which includes a fragment of at least 30 (50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 500, 550, 600, 650, 700, 800, 900, 1000, 1250, 1500, or 1695) nucleotides of the nucleotide sequence shown in SEQ ID NO:1, or SEQ ID NO:3, or the nucleotide sequence of the cDNA ATCC 209937, or a complement thereof.
The invention also features a nucleic acid molecule which includes a nucleotide sequence encoding a protein having an amino acid sequence that is at least 45% (or 55%, 65%, 75%, 85%, 95%, or 98%) identical to the amino acid sequence of SEQ ID NO:2, or the amino acid sequence encoded by the cDNA of ATCC 209937. In a preferred embodiment, DRT111 nucleic acid molecule has the nucleotide sequence shown SEQ ID NO:1, or SEQ ID NO:3, or the nucleotide sequence of the cDNA of ATCC 209937.
Also within the invention is a nucleic acid molecule which encodes a fragment of a polypeptide having the amino acid sequence of SEQ ID NO:2, the fragment including at least 15 (25, 30, 50, 100, 150, 300, or 400) contiguous amino acids of SEQ ID NO:2 or the polypeptide encoded by the cDNA of ATCC 209937.
The invention includes a nucleic acid molecule which encodes a naturally occurring allelic variant of a polypeptide having the amino acid sequence of SEQ ID NO:2 or an amino acid sequence encoded by the cDNA of ATCC 209937, wherein the nucleic acid molecule hybridizes to a nucleic acid molecule having the nucleotide sequence of SEQ ID NO:1 or SEQ ID NO:3 under stringent conditions.
Also within the invention are isolated nucleic acid molecules which encode a polypeptide having the amino acid sequence of SEQ ID NO:2; isolated nucleic acid molecules which encode a fragment of a polypeptide having the amino acid sequence of SEQ ID NO:2, wherein the fragment contains at least 15 contiguous amino acids of SEQ ID NO:2; and isolated nucleic acid molecules which encode naturally occurring allelic variants of a polypeptide including the amino acid sequence of SEQ ID NO: 2, wherein the nucleic acid molecule hybridizes to a nucleic acid molecule consisting of the nucleotide sequence of SEQ ID NO:1, SEQ ID NO:3, the complement of SEQ ID NO:1, or the complement of SEQ ID NO:3 under stringent conditions. These isolated nucleic acid molecules can have the nucleotide sequence of SEQ ID NO:1, SEQ ID NO:3, the complement of SEQ ID NO:1, or the complement of SEQ ID NO:3; the nucleotide sequence of SEQ ID NO:1, SEQ ID NO:3, the complement of SEQ ID NO:1 or, the complement of SEQ ID NO:3, wherein the “T”s are replaced with “U”s; or fragments of the foregoing that include at least 30 contiguous nucleotides of SEQ ID NO:1, SEQ ID NO:3, the complement of SEQ ID NO:1, or the complement of SEQ ID NO:3.
Another embodiment of the invention features isolated nucleic acid molecules which specifically detect DRT111 nucleic acid molecules relative to non-DRT111 nucleic acid molecules. For example, in one embodiment, such nucleic acid molecules hybridize under stringent conditions to a nucleic acid molecule having the nucleotide sequence of SEQ ID NO:1, SEQ ID NO:3, or the cDNA of ATCC 209937, or a complement thereof. In another embodiment, these nucleic acid molecules are at least 30 (50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 500, 550, 600, 650, 700, 800, 900, 1000, 1250, 1500, or 1695) nucleotides in length and hybridizes under stringent conditions to a nucleic acid molecule having the nucleotide sequence shown in SEQ ID NO:1, SEQ ID NO:3, the cDNA of ATCC 209937, or a complement thereof. In one embodiment, the invention provides an isolated nucleic acid molecule which is antisense to the coding strand of a DRT111 nucleic acid.
Also included in the invention are isolated nucleic acid molecules having a nucleotide sequence which is at least 55% identical to the nucleotide sequence of SEQ ID NO:1 or SEQ ID NO:3, or a complement thereof; tho

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