The molecular mechanism by which foreign DNA integrates into the human genome is 
poorly understood yet critical to many disease processes, including retroviral 
infection and carcinogenesis, and to gene therapy. We hypothesized that the 
mechanism of genomic integration may be similar to transposition in lower 
organisms. We identified a protein, termed Metnase, that has a SET domain and a 
transposase/nuclease domain. Metnase methylates histone H3 lysines 4 and 36, 
which are associated with open chromatin. Metnase increases resistance to 
ionizing radiation and increases nonhomologous end-joining repair of DNA 
doublestrand breaks. Most significantly, Metnase promotes integration of 
exogenous DNA into the genomes of host cells. Therefore, Metnase is a 
nonhomologous end-joining repair protein that regulates genomic integration of 
exogenous DNA and establishes a relationship among histone modification, DNA 
repair, and integration. The data suggest a model wherein Metnase promotes 
integration of exogenous DNA by opening chromatin and facilitating joining of 
DNA ends. This study demonstrates that eukaryotic transposase domains can have 
important cell functions beyond transposition of genetic elements.