Shared Mechanisms of RNA Biology

Our recent observation that most primary RNA polymerase II (polII) nascent transcripts (pre-mRNAs and long non-coding RNAs, lncRNAs) in animal cells fail to produce full gene-length transcripts when U1 snRNP (U1) is inhibited, revealed a new dimension in gene expression regulation. This essential U1 protective activity, which allows transcription to go farther (telescripting), suppresses premature cleavage and polyadenylation from cryptic signals (PASs) in introns. It is separate from U1’s splicing function; both depend on U1’s base pairing through its 5’ sequence, but 5’ modified U1 variants that cannot function in splicing are still effective in telescripting. Our studies have further shown that partial U1 inhibition with an antisense oligonucleotide to its 5’-end dose-dependently shortens mRNAs. Widespread mRNA shortening of 3’ untranslated regions (3’UTRs) occurs in cancer, proliferating cells, and activated immune cells and neurons. 3’UTRs have many mRNA regulatory elements, including miRNA targets that generally repress translation, and their removal contributes to oncogenicity. We have investigated the potential role of U1 telescripting in these phenomena. We found that moderate U1 decrease shortened 3’UTRs of hundreds of genes in HeLa cancer cells while its over-expression lengthened 3’UTRs of >2,000 genes that are already shortened in these cells. Concomitantly, U1 increase dose-dependently attenuated protein synthesis, cell migration and invasiveness, while its decrease drastically enhanced these cancer cell characteristics. U1-dependent 3’UTR length changes recapitulated cancer-causing miRNA target deregulation in numerous oncogenes. The strong correlation between U1’s bi-directional effects on nascent transcripts’ length and cell phenotype suggests that mRNA shortening in cancer can be explained by a deficit in U1 telescripting. Our findings establish telescripting’s major role in gene regulation. Notably, the ability of U1 modulation alone to profoundly modify cancer aggressiveness suggests telescripting as a potential target for moderating tumorigenesis.