Altering murine leukemia virus integration through disruption of the integrase and BET protein family interaction

Sriram Aiyer, G. V.T. Swapna, Nirav Malani, James M. Aramini, William M. Schneider, Matthew R. Plumb, Mustafa Ghanem, Ross C. Larue, Amit Sharma, Barbara Studamire, Mamuka Kvaratskhelia, Frederic D. Bushman, Gaetano T. Montelione, Monica J. Roth

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

We report alterations to the murine leukemia virus (MLV) integrase (IN) protein that successfully result in decreasing its integration frequency at transcription start sites and CpG islands, thereby reducing the potential for insertional activation. The host bromo and extraterminal (BET) proteins Brd2, 3 and 4 interact with the MLV IN protein primarily through the BET protein ET domain. Using solution NMR, protein interaction studies, and next generation sequencing, we show that the C-terminal tail peptide region of MLV IN is important for the interaction with BET proteins and that disruption of this interaction through truncation mutations affects the global targeting profile of MLV vectors. The use of the unstructured tails of gammaretroviral INs to direct association with complexes at active promoters parallels that used by histones and RNA polymerase II. Viruses bearing MLV IN C-terminal truncations can provide new avenues to improve the safety profile of gammaretroviral vectors for human gene therapy.

Original languageEnglish (US)
Pages (from-to)5917-5928
Number of pages12
JournalNucleic acids research
Volume42
Issue number9
DOIs
StatePublished - May 2014

All Science Journal Classification (ASJC) codes

  • Genetics

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