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Structure and regulation of the nuclear exosome targeting complex guides RNA substrates to the exosome

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  • Piotr Gerlach, Max Planck Institute of Biochemistry
  • ,
  • William Garland
  • Mahesh Lingaraju, Max Planck Institute of Biochemistry
  • ,
  • Anna Salerno-Kochan, Max Planck Institute of Biochemistry
  • ,
  • Fabien Bonneau, Max Planck Institute of Biochemistry
  • ,
  • Jérôme Basquin, Max Planck Institute of Biochemistry
  • ,
  • Torben Heick Jensen
  • Elena Conti, Max Planck Institute of Biochemistry

In mammalian cells, spurious transcription results in a vast repertoire of unproductive non-coding RNAs, whose deleterious accumulation is prevented by rapid decay. The nuclear exosome targeting (NEXT) complex plays a central role in directing non-functional transcripts to exosome-mediated degradation, but the structural and molecular mechanisms remain enigmatic. Here, we elucidated the architecture of the human NEXT complex, showing that it exists as a dimer of MTR4-ZCCHC8-RBM7 heterotrimers. Dimerization preconfigures the major MTR4-binding region of ZCCHC8 and arranges the two MTR4 helicases opposite to each other, with each protomer able to function on many types of RNAs. In the inactive state of the complex, the 3′ end of an RNA substrate is enclosed in the MTR4 helicase channel by a ZCCHC8 C-terminal gatekeeping domain. The architecture of a NEXT-exosome assembly points to the molecular and regulatory mechanisms with which the NEXT complex guides RNA substrates to the exosome.

Original languageEnglish
JournalMolecular Cell
Pages (from-to)2505-2518.e7
Publication statusPublished - 7 Jul 2022

Bibliographical note

Publisher Copyright:
© 2022 The Authors

    Research areas

  • conformational regulation, cryo-EM, domain swapping, helicase, NEXT, non-coding RNAs, pervasive transcription, RNA degradation, RNA exosome, RNA processing

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