LINE1 (L1) retrotransposons are non-viral mobile DNA elements that duplicate themselves by a "copy and paste" mechanism using an RNA intermediate. The Human Genome Project estimated that over 500,000 L1 copies occupy 17% of human DNA, although it is believed that only about 100 of these remain potentially active in any individual diploid genome. The L1 retrotransposition machinery has also been responsible for the insertion of over a million non-autonomous SINE elements (mainly Alus and SVAs), and thousands of processed pseudogenes. This mass of genomic baggage has had profound effects on genome organization and gene expression.
Retrotransposition is a complex process involving transcription of the full-length L1, RNA transport to the cytoplasm, translation of the bicistronic RNA, formation of an RNP particle followed by its re-import to the nucleus, targeting of the genomic integration site, nicking the DNA bottom strand, priming and reverse transcription, second strand synthesis, and resolution of the integrant. The many steps of retrotransposition, and the evolution of various cellular mechanisms for transposable element inhibition, predict a complex interaction between L1s and host proteins. Nevertheless, despite the significance of retrotransposons for human genome structure and function, much about their biology remains unknown.
Dr. Goodier’s explores the variability of retrotransposon-induced genome mutation, the mechanisms of retrotransposition, cellular components (protein and RNA) that interact with the L1, and the means by which the cell coexists with these genomic "parasites". To this end, we employ high-resolution microscopy, immunoprecipitation, mass spectroscopy, cell culture retrotransposition assays, mouse models, and high-throughput sequencing. Study of the mechanisms and control of LINE1 retrotransposition has the potential to yield up broader insights into cell biology and retroviral restriction.
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Terasaki N, Goodier JL, Cheung LE, Wang YJ, Kajikawa M, Kazazian HH Jr, Okada N. “In vitro screening for compounds that enhance human L1 mobilization.” PLoS One. 2013 Sep 11;8(9):e74629. doi: 10.1371/journal.pone.0074629. eCollection 2013.
Zhao K, Du J, Han X, Goodier JL, Li P, Zhou X, Wei W, Evans SL, Li L, Zhang W, Cheung LE, Wang G, Kazazian HH Jr, Yu XF. “Modulation of LINE-1 and Alu/SVA retrotransposition by Aicardi-Goutières syndrome-related SAMHD1.” Cell Rep. 2013 Sep 26;4(6):1108-15. doi: 10.1016/j.celrep.2013.08.019. Epub 2013 Sep 12.
Goodier JL, Cheung LE, Kazazian HH. “Mapping the LINE1 ORF1 protein interactome reveals associated inhibitors of human retrotransposition.” Nucleic Acids Research. 2013;41(15):7401-7419.
Goodier JL, Cheung LE, Kazazian HH Jr. “MOV10 RNA helicase is a potent inhibitor of retrotransposition in cells.” PLoS Genet. 2012;8(10):e1002941. doi: 10.1371/journal.pgen.1002941. Epub 2012 Oct 18.
Hancks DC, Goodier JL, Mandal PK, Cheung LE, Kazazian HH Jr. “Retrotransposition of marked SVA elements by human L1s in cultured cells.” Hum Mol Genet. 2011 Sep 1;20(17):3386-400. doi: 10.1093/hmg/ddr245. Epub 2011 Jun 2.