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 Vol. 102; no. 50; p. 18075
Main Authors: Lee, Suk-Hee, Oshige, Masahiko, Durant, Stephen T, Rasila, Kanwaldeep Kaur, Williamson, Elizabeth A, Ramsey, Heather, Kwan, Lori, Nickoloff, Jac A, Hromas, Robert
Format: Journal Article
Language:English
Published: United States 13.12.2005
Subjects:
Amino Acid Sequence
Cell Line
DNA - metabolism
DNA Methylation
DNA Primers
DNA Repair - genetics
DNA Repair Enzymes - genetics
Histone-Lysine N-Methyltransferase
Histones - metabolism
Humans
Methyltransferases - classification
Methyltransferases - genetics
Molecular Sequence Data
Protein Structure, Tertiary
Sequence Analysis, DNA
Virus Integration - genetics
Virus Integration - physiology
ISSN:0027-8424
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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.
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ISSN:0027-8424
DOI:10.1073/pnas.0503676102