Method for identifying compounds altering higher-order chromatin-dependent chromosome stability

Abstract

A method for identifying compounds that alter higher order chromatin dependent chromosome stability is based on determining the compounds' ability to modify a methyltransferase with Suv39h-like methyltransferase activity. The identified compounds are useful in therapy, in particular the therapy of human cancer and for contraception.

What is claimed is:  
     
         1 . A method for identifying a compound that alters higher order chromatin dependent chromosome stability in mitosis and meiosis, said method comprising incubating a substrate for a methyltransferase, in the presence of a methyl donor, with a methyltransferase with Suv39h-like methyltransferase activity, in the presence or absence of a test compound and determining whether the compound modulates the methyltransferase activity.  
     
     
         2 . The method of  claim 1 , wherein the methyltransferase with Suv39h-like activity methylates histone H3 at lysine 9.  
     
     
         3 . The method of  claim 2 , wherein the methyltransferase with Suv39h-like activity is murine Suv39h1 or human SUV39H1.  
     
     
         4 . The method of  claim 2 , wherein the methyltransferase with Suv39h-like activity is murine Suv39h2 or human SUV39H2.  
     
     
         5 . The method of any one of  claims 1  to  4 , wherein the substrate is histone H3 or an N-terminal fragment thereof that contains the methylation site at lysine 9.  
     
     
         6 . The method of  claim 5 , wherein the histone H3 N-terminal fragment has the amino acid sequence as set forth in SEQ ID NO:7.  
     
     
         7 . The method of any one of  claims 1  to  6 , wherein the methyl donor is methionine or S-adenosyl-L-methionine.  
     
     
         8 . The method of any one of  claims 1  to  7 , wherein the methyl group of the methyl donor carries a detectable label.  
     
     
         9 . The method of  claim 8 , wherein the methyl donor carries a chromogenic label and the methyltransferase activity is determined by measuring the change in colour upon transfer of the methyl group to the substrate.  
     
     
         10 . The method of  claim 8 , wherein the methyl donor carries a radioactive label and the methyltransferase activity is determined by measuring the radioactivity transferred to the substrate upon transfer of the methyl group.  
     
     
         11 . The method of any one of  claims 1  to  7 , wherein the methyltransferase activity is determined immunologically by quantifying the binding of an antibody specific for the methylation site of the substrate.  
     
     
         12 . The method of  claim 11  wherein the substrate carries a detectable label.  
     
     
         13 . An antibody that specifically recognises methylated lysine 9 in histone H3.  
     
     
         14 . The use of the H3-K9 methyl-specific antibody of  claim 13  for diagnosis of a human disease associated with aberrant gene expression and genomic instability through chromosome mis-segregation.  
     
     
         15 . A compound identified in a method defined in any one of  claims 1  to  12  for use in the the therapy of cancer.  
     
     
         16 . A compound identified in a method defined in any one of  claims 1  to  12  for contraception.  
     
     
         17 . The compound of  claim 15  for use in temporary male conception.