The SET Domain Protein Metnase Mediates Foreign DNA Integration and Links Integration to Nonhomologous End-Joining Repair

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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2005-12, Vol.102 (50), p.18075-18080
Main Authors: Lee, Suk-Hee, Masahiko Oshige, Stephen T. Durant, Kanwaldeep Kaur Rasila, Williamson, Elizabeth A., Ramsey, Heather, Lori Kwan, Nickoloff, Jac A., Robert Hrornas
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Amino acids
Biological Sciences
Cell Line
Chromatin
DNA
DNA - metabolism
DNA Methylation
DNA Primers
DNA repair
DNA Repair - genetics
DNA Repair Enzymes - genetics
Gene therapy
Genetic transposition
Genetic vectors
Genetics
Genomes
Genomics
Histone-Lysine N-Methyltransferase
Histones
Histones - metabolism
Humans
Methyltransferases - classification
Methyltransferases - genetics
Molecular Sequence Data
Plasmids
Protein Structure, Tertiary
Proteins
Sequence Analysis, DNA
Small interfering RNA
Virus Integration - genetics
Virus Integration - physiology
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0503676102