Non-coding RNAs affecting genomic stability

Several classes of non-coding RNAs (ncRNAs), arbitrarily grouped into short (<200 nucleotides) and long (>200 nucleotides) ncRNAs, have been identified so far, and each class differs in their origin, biogenesis and the mode of action. Here, we highlight the classes of ncRNAs that are fairly well characterized and/or have been implicated in maintaining genomic stability (see the table).

miRNAs

microRNAs (miRNAs) are short ncRNAs that are encoded in intronic regions of protein-coding genes or intergenic regions of the genome. Similarly to transcription factors, miRNAs affect a diverse range of cellular functions by regulating gene expression. The primary transcripts (pri-miRNAs) are processed in the nucleus by the Drosha microprocessor complex to generate ~70 base pair stem–loop precursor forms (pre-miRNAs). These are then exported to the cytoplasm by exportin 5 and further processed by Dicer into mature (~22 nucleotide) products. Mature miRNAs are incorporated in the RNA-induced silencing complex (RISC), which includes the Argonaute (AGO) and GW182 protein families, and loaded onto target transcripts. Typically, the nucleotides 2–8 at the 5′ end of the miRNA (termed the seed region) pairs perfectly with sequences in the 3′ untranslated region (UTR) of the target mRNA, and the rest of the miRNA–mRNA interaction is discontinuous. miRNAs mediate post-transcriptional gene silencing by inhibiting translation or by inducing degradation of target transcripts.

piRNAs

PIWI-interacting RNAs (piRNAs) form the largest class of small ncRNAs (26–31 nucleotides) and act as cofactors for the AGO-family protein PIWI. PIWI–piRNA complexes specifically target and silence transposable elements in germline cells to maintain genomic stability. piRNAs possess a predominant uridine at their 5′ end and are generated in a Dicer- and Drosha-independent manner. They are transcribed from piRNA clusters, intergenic repetitive elements or transposons and processed by unknown mechanisms. A complex between AGO3 and the sense piRNA can cleave antisense piRNA transcripts to generate a secondary functional piRNA. Similarly to miRNAs, piRNA can associate with target mRNAs and induce their degradation, but they can also mediate heterochromatin silencing and DNA methylation.

lncRNAs

Long non-coding RNAs (lncRNAs) (>200 nucleotides) represent the largest group of mammalian ncRNA transcripts, with tens of thousands of different species. They are involved in a broad range of processes, including epigenetic regulation, transcriptional and post-transcriptional regulation, RNA splicing and editing, telomere function, development, cancer and other diseases. lncRNAs are encoded in large intergenic loci or regions overlapping protein-coding genes, and they resemble mRNAs in that most are capped, spliced, polyadenylated and transcribed by RNA polymerase II. lncRNAs that are transcribed from intergenic regions constitute the specific class of long intergenic non-coding RNAs (lincRNAs). Some lncRNAs are encoded in transcribed ultraconserved regions (T-UCR; which are genomic elements that are highly conserved in mouse, rat and human genomes). T-UCRs are derived from intragenic or intergenic regions with a strong strand preference. Variations in T-UCR expression have been observed in several malignancies and, similarly to miRNAs, T-UCRs are frequently associated with fragile sites and various types of cancer-associated genomic regions.

  • Chowdhury D, Choi YE, Brault ME. (2013) Box 2 – Charity begins at home: non-coding RNA functions in DNA repair. Nature Reviews Molecular Cell Biology [Epub ahead of print]. [article]

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