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

Laura Williamson; Marco Saponaro; Stefan Boeing; Philip East; Richard Mitter; Theodoros Kantidakis; Gavin P. Kelly; Anna Lobley; Jane Walker; Bradley Spencer-Dene; Michael Howell; Aengus Stewart; Jesper Q. Svejstrup

doi:10.1016/j.cell.2017.01.019

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

Laura Williamson
, Marco Saponaro
, Stefan Boeing
, Philip East
, Richard Mitter
, Theodoros Kantidakis
, Gavin P. Kelly
, Anna Lobley
, Jane Walker
, Bradley Spencer-Dene
, Michael Howell
, Aengus Stewart
, Jesper Q. Svejstrup^*

^*Corresponding author for this work

The Francis Crick Institute
University College Birmingham
Mechanisms of Transcription Laboratory

Research output: Contribution to journal › Article › peer-review

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Abstract

The 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.

Original language	English
Pages (from-to)	843-855.e13
Journal	Cell
Volume	168
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2017.01.019
Publication status	Published - 23 Feb 2017

Bibliographical note

Funding

This work was supported by the Francis Crick Institute (that receives its core funding from Cancer Research UK [FC001166], the UK Medical Research Council [FC001166], and the Wellcome Trust [FC001166]) and by grants from the European Research Council, Agreements 693327 (TRANSDAM) and 268797 (TRANSINTEG). We thank The Francis Crick Advanced Sequencing Facility, the Cell Services Facility, the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics (funded by Wellcome Trust grant 090532/Z/09/Z) for expression array analysis, and Yang Shi for the kind gift of ASCC3 antibody. Peter Verrijzer and members of the Svejstrup laboratory are thanked for comments on the manuscript.

Keywords

alternative last exon splicing
ASCC3
DNA damage response
lncRNA
non-coding RNA
RNA polymerase II
transcript elongation
UV-irradiation

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10.1016/j.cell.2017.01.019Licence: CC BY 3.0

UV Irradiation Induces a Non-coding RNA that Functionally Opposes
© 2017 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Final published version, 3.06 MBLicence: CC BY 3.0

Cite this

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

abstract = "The 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.",

keywords = "alternative last exon splicing, ASCC3, DNA damage response, lncRNA, non-coding RNA, RNA polymerase II, transcript elongation, UV-irradiation",

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AU - Saponaro, Marco

AU - Boeing, Stefan

AU - East, Philip

AU - Mitter, Richard

AU - Kantidakis, Theodoros

AU - Kelly, Gavin P.

AU - Lobley, Anna

AU - Walker, Jane

AU - Spencer-Dene, Bradley

AU - Howell, Michael

AU - Stewart, Aengus

AU - Svejstrup, Jesper Q.

PY - 2017/2/23

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N2 - The 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.

AB - The 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.

KW - alternative last exon splicing

KW - ASCC3

KW - DNA damage response

KW - lncRNA

KW - non-coding RNA

KW - RNA polymerase II

KW - transcript elongation

KW - UV-irradiation

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

Abstract

Bibliographical note

Funding

Keywords

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