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PMID: 16332963 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural

The SET domain protein Metnase mediates foreign DNA integration and links integration to nonhomologous end-joining repair.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 102 ·No. 50 ·2005-12-13 ·Pages 18075-80

Lee SH, Oshige M, Durant ST, Rasila KK, Williamson EA, Ramsey H, Kwan L, Nickoloff JA, Hromas R

Abstract

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.

MeSH Terms
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,genetics Molecular Sequence Data Protein Structure, Tertiary Sequence Analysis, DNA Virus Integration/genetics,physiology
Chemicals
DNA Primers Histones DNA Methyltransferases Histone-Lysine N-Methyltransferase SETMAR protein, human DNA Repair Enzymes
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Lee Suk-Hee
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, 46202, USA.
Oshige Masahiko
Durant Stephen T
Rasila Kanwaldeep Kaur
Williamson Elizabeth A
Ramsey Heather
Kwan Lori
Nickoloff Jac A
Hromas Robert
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0503676102
Published
2005-12-13
Epub
2005-00-06
Pages
18075-80
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1312370
Subset
IM
Grants
NCI NIH HHS · CA100862 · United States
NCI NIH HHS · R01 CA092111 · United States
NHLBI NIH HHS · HL075783 · United States
NCI NIH HHS · CA102283 · United States
NCI NIH HHS · R01 CA102283 · United States
NCI NIH HHS · CA92111 · United States
NCI NIH HHS · R01 CA100862 · United States
NHLBI NIH HHS · R01 HL075783 · United States
Databases
GENBANK
AY952295
External Links
PubMed source DOI: 10.1073/pnas.0503676102 PMC Full Text View journal details
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