UV Irradiation Induces a Non-coding RNA that Functionally Opposes the Protein Encoded by the Same Gene

Abstract

SummaryThe transcription-related DNA damage response was analyzed on a genome-wide scale with great spatial and temporal resolution. Upon UV irradiation, a slowdown of transcript elongation and restriction of gene activity to the promoter-proximal ∼25 kb is observed. This is associated with a shift from expression of long mRNAs to shorter isoforms, incorporating alternative last exons (ALEs) that are more proximal to the transcription start site. Notably, this includes a shift from a protein-coding ASCC3 mRNA to a shorter ALE isoform of which the RNA, rather than an encoded protein, is critical for the eventual recovery of transcription. The non-coding ASCC3 isoform counteracts the function of the protein-coding isoform, indicating crosstalk between them. Thus, the ASCC3 gene expresses both coding and non-coding transcript isoforms with opposite effects on transcription recovery after UV-induced DNA damage.

The functions and unique features of long intergenic non-coding RNA

“…A fascinating recent example is the switch induced by ultraviolet irradiation from the expression of long, protein-coding ASCC3 transcripts to the expression of a short non-coding ASCC3 isoform. The non-coding isoform antagonizes the ASCC3 protein to facilitate transcriptional recovery following ultraviolet-induced damage 24 (FIG. 4c).…”

“…Ultraviolet irradiation leads to slower transcription at the ASCC3 locus and induces the use of an alternative, proximal last exon and the expression of a short, non-coding RNA. This non-coding RNA antagonizes the function of the ASCC complex, thereby promoting recovery from ultraviolet-induced DNA damage 24 . Pol II, RNA polymerase II; U1, U1 small nuclear RNA.…”

DDX54 regulates transcriptome dynamics during DNA damage response

“…Interestingly, these include proteins with previous links to DNA repair such as RECQL4 (Singh et al 2010), PARP14 (Nicolae et al 2015), CHD4 (O'Shaughnessy and Hendrich 2013), and ASCC3 ( Fig. 1J; Dango et al 2011;Williamson et al 2017). Our data set of 266 proteins with increased binding to poly(A) + RNA upon genotoxic stress provides a catalog (Supplemental Table S1) of candidate trans-acting DDR factors and highlights the importance of RBPs in the DDR.…”

CRISPR-Mediated Base Editing Enables Efficient Disruption of Eukaryotic Genes through Induction of STOP Codons

“…Indeed, by disrupting gene ORFs without altering gene structures, (1) iSTOP could allow the separation of coding from non-coding functions of genes, such as ASCC3 (Williamson et al, 2017), that encode for both proteins and long non-coding RNAs (lncRNAs), and lncRNAs that contain putative alternative short ORFs (Andrews and Rothnagel, 2014). In addition, (2) iSTOP could be employed to incorporate modified or non-natural amino acids into proteins using tRNAs that suppress the newly introduced STOP codons (Elsässer et al, 2016).…”