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, Lydia; Goldstrohm, Aaron C.; Trievel, Raymond C.

doi:10.1093/nar/gky412

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

Journal Article · 31 May 2018 · Nucleic Acids Research

DOI: https://doi.org/10.1093/nar/gky412 · OSTI ID:1439776

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

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.

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Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1439776

Alternate ID(s):: OSTI ID: 1460872

Journal Information:: Nucleic Acids Research, Journal Name: Nucleic Acids Research Journal Issue: 12 Vol. 46; ISSN 0305-1048

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United Kingdom

Language:: English

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