Human DNA Ligase IV

Abstract

A human DNA Ligase IV polypeptide and DNA (RNA) encoding such polypeptide and a procedure for producing such polypeptide by recombinant techniques is disclosed. Also disclosed are methods for utilizing such polypeptide via gene therapy for the treatment of disorders associated with a defect in DNA Ligase IV. Antagonists against such polypeptides and their use as a therapeutic to destroy unwanted cells are also disclosed. Diagnostic assays to detect mutant DNA Ligase IV genes are also disclosed.

What is claimed is:  
     
         1 . An isolated polynucleotide comprising a member selected from the group consisting of: 
 (a) a polynucleotide encoding the polypeptide as set forth in SEQ ID NO:2;    (b) a polynucleotide capable of hybridizing to and which is at least 70% identical to the polynucleotide of (a); and    (c) a polynucleotide fragment of the polynucleotide of (a) or (b).    
     
     
         2 . The polynucleotide of  claim 1  wherein the polynucleotide is DNA.  
     
     
         3 . The polynucleotide of  claim 2  which encodes the polypeptide as set forth in SEQ ID NO:2.  
     
     
         4 . The polynucleotide of  claim 2  comprising the nucleotide sequence of SEQ ID NO:1 from nucleotide 1 to 3325.  
     
     
         5 . The polynucleotide of  claim 2  comprising the nucleotide sequence of SEQ ID NO:1 from nucleotide 232 to 3325.  
     
     
         6 . An isolated polynucleotide comprising a member selected from the group consisting of: 
 (a) a polynucleotide which encodes a mature polypeptide encoded by the DNA contained in ATCC Deposit No. 75880;    (b) a polynucleotide which encodes a polypeptide expressed by the DNA contained in ATCC Deposit No. 75880;    (c) a polynucleotide capable of hybridizing to and which is at least 70% identical to the polynucleotide of (a) or (b); and    (d) a polynucleotide fragment of the polynucleotide of (a), (b) or (c).    
     
     
         7 . A vector containing the DNA of  claim 2 .  
     
     
         8 . A host cell genetically engineered with the vector of  claim 7 .  
     
     
         9 . A process for producing a polypeptide comprising: expressing from the host cell of  claim 8  the polypeptide encoded by said DNA.  
     
     
         10 . A process for producing cells capable of expressing a polypeptide comprising transforming or transfecting the cells with the vector of  claim 7 .  
     
     
         11 . A polypeptide selected from the group consisting of (i) a polypeptide having the deduced amino acid sequence of SEQ ID NO:2 and fragments, analogs and derivatives thereof; (ii) a polypeptide encoded by the cDNA of ATCC Deposit No. 75880 and fragments, analogs and derivatives of said polypeptide.  
     
     
         12 . A compound effective as an agonist for the polypeptide of  claim 11 .  
     
     
         13 . A compound effective as an antagonist against the polypeptide of  claim 11 .  
     
     
         14 . A method for the treatment of a patient having need of hABH comprising: administering to the patient a therapeutically effective amount of the polypeptide of  claim 11 .  
     
     
         15 . The method of  claim 14  wherein said therapeutically effective amount of the polypeptide is administered by providing to the patient DNA encoding said polypeptide and expressing said polypeptide in vivo.  
     
     
         16 . A method for the treatment of a patient having need of hABH comprising: administering to the patient a therapeutically effective amount of the compound of  claim 12 .  
     
     
         17 . A method for the treatment of a patient having need to inhibit DNA Ligase IV comprising: administering to the patient a therapeutically effective amount of the antagonist of  claim 13 .  
     
     
         18 . A process for diagnosing a disease or a susceptibility to a disease related to expression of the polypeptide of  claim 11  comprising: 
 determining a mutation in the nucleic acid sequence encoding said polypeptide.  
 
     
     
         19 . A diagnostic process comprising: 
 analyzing for the presence of the polypeptide of  claim 11  in a sample derived from a host.    
     
     
         20 . A method for identifying antagonists and agonists comprising: 
 combining DNA Ligase IV, DNA having single-strand breaks and a compound to be screened under conditions where the single-strand break would be repaired by the DNA Ligase IV; and    determining if the compound enhances or blocks the repair.