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

Piotr Gerlach*, William Garland, Mahesh Lingaraju, Anna Salerno-Kochan, Fabien Bonneau, Jérôme Basquin, Torben Heick Jensen, Elena Conti

*Corresponding author af dette arbejde

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Abstract

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.

OriginalsprogEngelsk
TidsskriftMolecular Cell
Vol/bind82
Nummer13
Sider (fra-til)2505-2518.e7
ISSN1097-2765
DOI
StatusUdgivet - 7 jul. 2022

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