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

Suk Hee Lee, Masahiko Oshige, Stephen T. Durant, Kanwaldeep Kaur Rasila, Elizabeth A. Williamson, Heather Ramsey, Lori Kwan, Jac A. Nickoloff, Robert A Hromas

Research output: Contribution to journalArticle

92 Citations (Scopus)

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 double-strand 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.

Original languageEnglish (US)
Pages (from-to)18075-18080
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number50
DOIs
StatePublished - Dec 13 2005
Externally publishedYes

Fingerprint

DNA
Transposases
Chromatin
DNA End-Joining Repair
Histone Code
Double-Stranded DNA Breaks
Human Genome
Ionizing Radiation
DNA Repair
Genetic Therapy
Histones
Lysine
Carcinogenesis
Proteins
Protein Domains
Genome
Infection

Keywords

  • DNA repair
  • Histone methylation

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

The SET domain protein Metnase mediates foreign DNA integration and links integration to nonhomologous end-joining repair. / Lee, Suk Hee; Oshige, Masahiko; Durant, Stephen T.; Rasila, Kanwaldeep Kaur; Williamson, Elizabeth A.; Ramsey, Heather; Kwan, Lori; Nickoloff, Jac A.; Hromas, Robert A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 50, 13.12.2005, p. 18075-18080.

Research output: Contribution to journalArticle

Lee, Suk Hee ; Oshige, Masahiko ; Durant, Stephen T. ; Rasila, Kanwaldeep Kaur ; Williamson, Elizabeth A. ; Ramsey, Heather ; Kwan, Lori ; Nickoloff, Jac A. ; Hromas, Robert A. / The SET domain protein Metnase mediates foreign DNA integration and links integration to nonhomologous end-joining repair. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 50. pp. 18075-18080.
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