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Review
. 2022 Mar;47(3):206-217.
doi: 10.1016/j.tibs.2021.08.003. Epub 2021 Sep 3.

Who let the DoGs out? - biogenesis of stress-induced readthrough transcripts

Nicolle A Rosa-Mercado  1 , Joan A Steitz  2
Affiliations
Review

Who let the DoGs out? - biogenesis of stress-induced readthrough transcripts

Nicolle A Rosa-Mercado et al. Trends Biochem Sci. 2022 Mar.

Abstract

Readthrough transcription caused by inefficient 3'-end cleavage of nascent mRNAs has emerged as a hallmark of the mammalian cellular stress response and results in the production of long noncoding RNAs known as downstream-of-gene (DoG)-containing transcripts. DoGs arise from around 10% of human protein-coding genes and are retained in the nucleus. They are produced minutes after cell exposure to stress and can be detected hours after stress removal. However, their biogenesis and the role(s) that DoGs or their production play in the cellular stress response are incompletely understood. We discuss findings that implicate host and viral proteins in the mechanisms underlying DoG production, as well as the transcriptional landscapes that accompany DoG induction under different stress conditions.

Keywords: 3′-end cleavage; cellular stress; long noncoding RNAs; readthrough transcription; transcription termination.

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Conflict of interest statement

Declaration of interests The authors declare no conflicts of interest.

Figures

Figure 1:
Figure 1:. Cellular stress induces the production of nuclear-retained downstream-of-gene (DoG) RNAs.
After synthesis, many DoGs remain close to their sites of transcription, while others are released into the nucleoplasm [13, 25]. DoG production can lead to the invasive transcription of neighboring genes (read-in genes) [16, 19, 23]. Genes that are free of read-in transcription are referred to as clean genes. DoG RNAs have been detected at similar levels in both polyadenylated and unpolyadenylated forms [12].
Figure 2:
Figure 2:. Characteristics of downstream-of-gene (DoG)-producing genes.
A canonical poly(A) signal is found within 50 base pairs of the 3´-end of 79 percent of non-DoG genes and 61 percent of genes that produce DoGs upon HSV-1 infection [19]. Similarly, comparing the frequency of appearance of the canonical poly(A) signal in the sense versus the antisense strand across the region 5 kb downstream of the annotated transcription end sites (TES) of DoG-producing genes induced by hyperosmotic stress revealed that this sequence is less prevalent at DoG producing genes compared to non-DoG genes (ratio of 0.8 at DoG-producing genes versus 1.1 in non-DoG genes) [13]. The estimated frequency of the canonical poly(A) signal, AATAAA, and of the weaker ATTAAA are depicted in the figure. Additionally, DoG regions are slightly enriched for histone marks that favor transcription elongation throughout the first 5 kb after their annotated TES (H3K36me3 and H3K79me2). DoG regions are also enriched for histone marks typically found in intergenic regions, such as H3K4me1 and H3K27ac [15].
Figure 3:
Figure 3:. Termination factors involved in downstream-of-gene (DoG) production.
(Top) Under homeostasis, components of the cleavage and polyadenylation (CPA) machinery mediate the 3´-end formation of protein-coding gene transcripts [74]. The Integrator complex regulates RNA output near transcription start sites [59, 60, 61] and transcripts that continue to be elongated are normally cleaved and polyadenylated at the 3´-end. (Middle) Upon hyperosmotic stress, the interaction between Pol II and Integrator is disrupted and DoG-production is observed [12]. Dysregulated occupancy of CPA components upon hyperosmotic stress has been reported [40, 51]. However, whether this deficit directly affects DoG-producing genes remains unclear. The uncertain (yet likely) loss of CPA factors during DoG production is indicated in the figure with a question mark. Differential gene expression observed upon salt stress does not dictate a gene’s ability to produce DoGs. (Bottom) After Influenza A or HSV-1 infection, viral proteins NS1 and ICP27, respectively, sequester subunits of the CPA machinery leading to DoG biogenesis [63, 64]. Upon cellular stress, three types of transcripts have been detected and are, therefore, represented throughout this figure: mature mRNAs, polyadenylated DoGs, and non-polyadenylated DoGs.
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