Regulation of Transposable Elements by microRNAs in Cancer

Abstract

Transposable elements (TEs) comprise nearly half of the human genome, and their ongoing activity continues to impact its structure and function. The only TEs that remain autonomously active are Long INterspersed Elements class 1 (LINE-1s or L1s) retrotransposons, whose 500,000 copies account for ~17% of our genome. Only 80-100 L1s retain the ability to mobilize, and are therefore called Retrotransposition-Competent L1s (RC-L1s). RC-L1s are 6kb long and encode two proteins that are required for their mobilization: L1-ORF1p, an RNA binding protein with chaperone activity, and L1-ORF2p, with endonuclease and reverse transcriptase activities. RC-L1s mobilize via a copy-and-paste mechanism, generating new insertions by reverse transcription of an intermediate RNA. At present, over one hundred disease-causing insertions have been reported. Altogether, this Thesis represents a contribution to the fields of mobile genetic elements and miRNAs, as well as to cancer biology. In fact, we uncover a new role for the tumor suppressor miRNA let-7 family: maintaining somatic genome integrity by restricting L1 retrotransposition.