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A novel Smg6 mouse model reveals regulation of circadian period and daily CRY2 accumulation through the nonsense-mediated mRNA decay pathway


Katsioudi, Georgia; Dreos, René; Arpa, Enes S; Gaspari, Sevasti; Liechti, Angelica; Sato, Miho; Gabriel, Christian H; Kramer, Achim; Brown, Steven A; Gatfield, David (2022). A novel Smg6 mouse model reveals regulation of circadian period and daily CRY2 accumulation through the nonsense-mediated mRNA decay pathway. ArXiv.org 498406, Cornell University.

Abstract

Nonsense-mediated mRNA decay (NMD) has been intensively studied as a surveillance pathway that degrades erroneous transcripts arising from mutations or RNA processing errors. While additional roles in controlling regular mRNA stability have emerged, possible functions in mammalian physiology in vivo have remained unclear. Here, we report a novel conditional mouse allele that allows converting the NMD effector nuclease SMG6 from wild-type to nuclease domain-mutant protein. We analyzed how NMD downregulation affects the function of the circadian clock, a system known to require rapid mRNA turnover. We uncover strong lengthening of free-running circadian periods for liver and fibroblast clocks, and direct NMD regulation of Cry2 mRNA, encoding a key transcriptional repressor within the rhythm-generating feedback loop. In the entrained livers of Smg6 mutant animals we reveal transcriptome-wide alterations in daily mRNA accumulation patterns, altogether expanding the known scope of NMD regulation in mammalian gene expression and physiology.

Abstract

Nonsense-mediated mRNA decay (NMD) has been intensively studied as a surveillance pathway that degrades erroneous transcripts arising from mutations or RNA processing errors. While additional roles in controlling regular mRNA stability have emerged, possible functions in mammalian physiology in vivo have remained unclear. Here, we report a novel conditional mouse allele that allows converting the NMD effector nuclease SMG6 from wild-type to nuclease domain-mutant protein. We analyzed how NMD downregulation affects the function of the circadian clock, a system known to require rapid mRNA turnover. We uncover strong lengthening of free-running circadian periods for liver and fibroblast clocks, and direct NMD regulation of Cry2 mRNA, encoding a key transcriptional repressor within the rhythm-generating feedback loop. In the entrained livers of Smg6 mutant animals we reveal transcriptome-wide alterations in daily mRNA accumulation patterns, altogether expanding the known scope of NMD regulation in mammalian gene expression and physiology.

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Additional indexing

Item Type:Working Paper
Communities & Collections:04 Faculty of Medicine > Institute of Pharmacology and Toxicology
07 Faculty of Science > Institute of Pharmacology and Toxicology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:3 July 2022
Deposited On:08 Feb 2023 16:14
Last Modified:05 Jun 2024 11:55
Series Name:ArXiv.org
Number of Pages:33
ISSN:2331-8422
OA Status:Green
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1101/2022.07.01.498406
Related URLs:https://www.zora.uzh.ch/id/eprint/230135/
https://doi.org/10.1126/sciadv.ade2828
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)