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-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 G(1) phase of the cell cycle and retarded growth of transposase-expressing cells. G(1) slowdown is associated with a decrease of cyclin D1/cdk4-specific phosphorylation of the retinoblastoma protein. Both cyclin D1 down-regulation and the G(1) slowdown induced by the transposase require Miz-1. A temporary G(1) arrest enhances transposition, suggesting that SB transposition is favored in the G(1) 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 G(1) slowdown is probably a selfish act on the transposon's part to maximize the chance for a successful transposition event.
Max Delbrück Center for Molecular Medicine, D-13092 Berlin, Germany.
Oliver
O
Walisko
Zsuzsanna
Z
Izsvák
Kornélia
K
Szabó
Christopher D
CD
Kaufman
Steffi
S
Herold
Zoltán
Z
Ivics
D000818:Animals; D016466:CHO Cells; D002453:Cell Cycle / Q000502:physiology*; D006224:Cricetinae; D019938:Cyclin D1 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D016193:G1 Phase / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D051741:Kruppel-Like Transcription Factors; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000737:chemistry / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019895:Transposases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; C107961:ZBTB17 protein, human; D019938:Cyclin D1; D019895:Transposases; C494471:sleeping beauty transposase, human