Sleeping Beauty Transposase Modulates Cell-Cycle Progression through Interaction with Miz-1

We used the Sleeping Beauty (SB) transposable element as a tool to probe transposon-host cell interactions in vertebrates. The Miz-1 transcription factor was identified as an interactor of the SB transposase in a yeast two-hybrid screen. Through its association with Miz-1, the SB transposase down-re...

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Published in:	Proceedings of the National Academy of Sciences - PNAS 2006-03, Vol.103 (11), p.4062-4067
Main Authors:	Walisko, Oliver, Izsvák, Zsuzsanna, Szabó, Kornélia, Kaufman, Christopher D., Herold, Steffi, Ivics, Zoltán
Format:	Article
Language:	eng
Subjects:	Animals Antibodies Antimony Biochemistry Biological Sciences Cell cycle Cell Cycle - physiology Cell growth Cell lines CHO Cells Cricetinae Cyclin D1 - metabolism Cyclins Deoxyribonucleic acid DNA DNA-Binding Proteins - chemistry DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Down-Regulation G1 Phase - physiology Gene expression Genetic transposition HeLa Cells Humans In Vitro Techniques Interphase Kruppel-Like Transcription Factors Oligonucleotide Array Sequence Analysis Phosphorylation Recombinant Fusion Proteins - chemistry Recombinant Fusion Proteins - genetics Recombinant Fusion Proteins - metabolism Retinoblastoma Protein - chemistry Retinoblastoma Protein - metabolism Transcription Factors - chemistry Transcription Factors - genetics Transcription Factors - metabolism Transposases - chemistry Transposases - genetics Transposases - metabolism Transposons Two-Hybrid System Techniques Vertebrates Zinc Fingers
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Summary:	We used the Sleeping Beauty (SB) transposable element as a tool to probe transposon-host cell interactions in vertebrates. The Miz-1 transcription factor was identified as an interactor of the SB transposase in a yeast two-hybrid screen. Through its association with Miz-1, the SB transposase down-regulates cyclin D1 expression in human cells, as evidenced by differential gene expression analysis using microarray hybridization. Down-regulation of cyclin D1 results in a prolonged G1 phase of the cell cycle and retarded growth of transposase-expressing cells. G1 slowdown is associated with a decrease of cyclin D1/cdk4-specific phosphorylation of the retinoblastoma protein. Both cyclin D1 down-regulation and the G1 slowdown induced by the transposase require Miz-1. A temporary G1 arrest enhances transposition, suggesting that SB transposition is favored in the G₁ phase of the cell cycle, where the nonhomologous end-joining pathway of DNA repair is preferentially active. Because nonhomologous end-joining is required for efficient SB transposition, the transposase-induced G1 slowdown is probably a selfish act on the transposon's part to maximize the chance for a successful transposition event.
ISSN:	0027-8424 1091-6490