The structure of human Nocturnin reveals a conserved ribonuclease domain that represses target transcript translation and abundance in cells

Elizabeth T. Abshire, Jennifer Chasseur, Jennifer A. Bohn, Paul A. Del Rizzo, Peter L. Freddolino, Aaron Goldstrohm, Raymond C. Trievel

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

The circadian protein Nocturnin (NOCT) belongs to the exonuclease, endonuclease and phosphatase superfamily and is most similar to the CCR4-class of deadenylases that degrade the poly-adenosine tails of mRNAs. NOCT-deficient mice are resistant to high-fat diet induced weight gain, and exhibit dysregulation of bone formation. However, the mechanisms by which NOCT regulates these processes remain to be determined. Here, we describe a pair of high-resolution crystal structures of the human NOCT catalytic domain. The active site of NOCT is highly conserved with other exoribonucleases, and when directed to a transcript in cells, NOCT can reduce translation and abundance of that mRNA in a manner dependent on key active site residues. In contrast to the related deadenylase CNOT6L, purified recombinant NOCT lacks in vitro ribonuclease activity, suggesting that unidentified factors are necessary for enzymatic activity. We also find the ability of NOCT to repress reporter mRNAs in cells depends upon the 3′ end of the mRNA, as reporters terminating with a 3′ MALAT1 structure cannot be repressed by NOCT. Together, these data demonstrate that NOCT is an exoribonuclease that can degrade mRNAs to inhibit protein expression, suggesting a molecular mechanism for its regulatory role in lipid metabolism and bone development.

Original languageEnglish (US)
Pages (from-to)6257-6270
Number of pages14
JournalNucleic acids research
Volume46
Issue number12
DOIs
StatePublished - Jul 6 2018

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Ribonucleases
Exoribonucleases
Catalytic Domain
Messenger RNA
nocturnin
Exonucleases
Endonucleases
Bone Development
Protein Biosynthesis
High Fat Diet
Lipid Metabolism
Phosphoric Monoester Hydrolases
Osteogenesis
Adenosine
Weight Gain
Tail
Proteins

PubMed: MeSH publication types

  • Journal Article

Cite this

The structure of human Nocturnin reveals a conserved ribonuclease domain that represses target transcript translation and abundance in cells. / Abshire, Elizabeth T.; Chasseur, Jennifer; Bohn, Jennifer A.; Del Rizzo, Paul A.; Freddolino, Peter L.; Goldstrohm, Aaron; Trievel, Raymond C.

In: Nucleic acids research, Vol. 46, No. 12, 06.07.2018, p. 6257-6270.

Research output: Contribution to journalArticle

Abshire, Elizabeth T. ; Chasseur, Jennifer ; Bohn, Jennifer A. ; Del Rizzo, Paul A. ; Freddolino, Peter L. ; Goldstrohm, Aaron ; Trievel, Raymond C. / The structure of human Nocturnin reveals a conserved ribonuclease domain that represses target transcript translation and abundance in cells. In: Nucleic acids research. 2018 ; Vol. 46, No. 12. pp. 6257-6270.
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