A Reverse Transcriptase-dependent mechanism is active in early embryogenesis and in tumorigenesis.
Institute of Translational Pharmacology, Rome
Long Interspersed Nuclear Elements (LINE-1) and endogenous retroviruses represent the most abundant families of retrotransposable elements in mammalian genomes. They encode a reverse transcriptase (RT) protein as part of the ORF2. The RT is required for LINE-1’s own mobilization as well as that of non-autonomous Alu/SINE retrotrasposons. In past work we showed that LINE-1-derived ORF2p, encoding RT, is abundantly expressed in murine embryo early stages, and in murine and human cancers, while being virtually absent from normal somatic differentiated tissues. In parallel, we also detected a progressive increase of LINE-1 and SINE copy numbers in the genome of murine preimplantation embryo stages and in tumor progression. The increase in RT activity and retrotranpsosable elements is not simply circumstantial, but has functional roles. Indeed, we found that inhibition of LINE-1-encoded RT arrests early embryo development. In addition, it also inhibits cancer cell proliferation, promotes their differentiation and antagonizes tumor growth in animal models. In line with this, the nonnucleoside RT inhibitor efavirenz recently proved effective in a phase II trial with prostate carcinoma metastatic patients.
Part of our work has been devoted to get insight into the RT-dependen mechanism(s) implicated in early embyrogenesis and tumorigenesis. We have examined global expression profiles in native and RT-inhibited cells and find that: i) RT inhibition causes a global reprogramming of expression of coding genes, microRNAs (miRNAs) and genomic ultra conserved regions (UCRs), ii) Alu- and LINE-1-containing RNA:DNA hybrid molecules abundantly from in cancer but not in normal cells, nor in RT inhibitor-treated tumor cells. We therefore propose that the abundant RT in embryos and cancer cells reverse-transcribes RNA precursors, generating RNA:DNA hybrids that affect the overall production of various RNA classes, including regulatory miRNAs, with an ensuing impact on global gene expression. RT inhibition restores the ‘normal’ expression profiles of regulatory RNAs. Thus, LINE1-RT drives a regulatory mechanism required in early embryogenesis, which, when erroneously reactivated in adult life, drives cell transformation and tumorigenesis.
Type: EBI seminar
When: Tuesday 21 February 2017; 2:00pm to 3:00pm