Regulatory roles of LINE-1-encoded reverse transcriptase in cancer onset and progression

Abstract

LINE-1 retrotransposons encode the reverse transcriptase (RT) enzyme, required for their own mobility, the expression of which is inhibited in differentiated tissues while being active in tumors. Experimental evidence indicate that the inhibition of LINE-1-derived RT restores differentiation in cancer cells, inhibits tumor progression and yields globally reprogrammed transcription profiles. Newly emerging data suggest that LINE-1-encoded RT modulates the biogenesis of miRNAs, by governing the balance between the production of regulatory double-stranded RNAs and RNA:DNA hybrid molecules, with a direct impact on global gene expression. Abnormally high RT activity unbalances the transcriptome in cancer cells, while RT inhibition restores ‘normal’ miRNA profiles and their regulatory networks. This RT-dependent mechanism can target the myriad of transcripts - both coding and non-coding, sense and antisense - in eukaryotic transcriptomes, with a profound impact on cell fates. LINE-1-encoded RT emerges therefore as a key regulator of a previously unrecognized mechanism in tumorigenesis

Distinguishing epigenetic features of preneoplastic testis tissues adjacent to seminomas and nonseminomas

“…It is known that deregulation of retrotransposon expression may lead to neoplastic transformations in various types of cancers [28–30]. Therefore, we obtained integral methylation level of LINE-1 promoters in the samples under study to see whether expression level of PIWI genes impacts their function.…”

Novel Role of 3’UTR-Embedded Alu Elements as Facilitators of Processed Pseudogene Genesis and Host Gene Capture by Viral Genomes

“…Thus, if viral capture of host genes uses the same mechanism as PP genesis (the L1 machinery), it may occur either in germline or somatic tissues covering a broad cell spectrum. Gene hijacking by viruses may also occur in cancer cells, where L1 proteins could be very abundant [114]. We also speculate that the role of 3’UTR-embedded Alus facilitating the genesis of new retrocopies of lowly expressed genes may be important for some DNA viruses, as the incorporation to their genomes of lowly expressed cell-specific genes could be more useful for the virus that the capture of highly expressed housekeeping genes.…”

Improvement in the Selection of Patients for Anti-PD1 Immunotherapy in Non-Small Cell Lung Cancer (NSCLC) Analyzing Tumor Mutational Burden and Retrotransposon Activity as Possible New Biomarker of Effectiveness

“…In addition, the determinants of response to PD-1 blockade appear to be shaped by the genomic alter-inhibited in cancer cell lines using nonnucleoside inhibitors [23] and RNA interference (RNAi) methodology to down-regulate the expression of full-length RT-encoding LINE-1 elements [25]. RT inhibition affects the cancer transcriptome globally and may reduce proliferation of cancer cells and restores their "normal" phenotypes.…”

“…Each LINE-1 copy encodes a bicistronic RNA transcript which is translated into a 40 kDa RNA-binding protein (ORF-1) and a 150 kDa protein (ORF-2), the latter endowed with endonuclease and reverse transcriptase (RT) activities. As such, RT is the most highly repeated protein-coding sequence in the genome of higher eukaryotes and an essential component of the retrotransposition machinery, required not only for the mobilization of its own coding elements, but also for other non-autonomous retrotransposons, such as Alu and SVA [23]. Only in the last decade have roles of the LINE-1-encoded RT been recognized, both in embryogenesis and in tumorigenesis.…”