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Open AccessArticle

The Intrinsically Disordered C-Terminal Domain Triggers Nucleolar Localization and Function Switch of PARN in Response to DNA Damage

State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cells 2019, 8(8), 836; https://doi.org/10.3390/cells8080836
Received: 29 June 2019 / Revised: 23 July 2019 / Accepted: 29 July 2019 / Published: 5 August 2019
(This article belongs to the Special Issue Nucleolar Organization and Functions in Health and Disease)
Poly(A)-specific ribonuclease (PARN), a multifunctional multi-domain deadenylase, is crucial to the regulation of mRNA turnover and the maturation of various non-coding RNAs. Despite extensive studies of the well-folding domains responsible for PARN catalysis, the structure and function of the C-terminal domain (CTD) remains elusive. PARN is a cytoplasm–nucleus shuttle protein with concentrated nucleolar distribution. Here, we identify the nuclear and nucleolar localization signals in the CTD of PARN. Spectroscopic studies indicated that PARN-CTD is intrinsically disordered with loosely packed local structures/tertiary structure. Phosphorylation-mimic mutation S557D disrupted the local structure and facilitated the binding of the CTD with the well-folded domains, with no impact on PARN deadenylase activity. Under normal conditions, the nucleolus-residing PARN recruited CBP80 into the nucleoli to repress its deadenylase activity, while DNA damage-induced phosphorylation of PARN-S557 expelled CBP80 from the nucleoli to discharge activity inhibition and attracted nucleoplasm-located CstF-50 into the nucleoli to activate deadenylation. The structure switch-induced function switch of PARN reshaped the profile of small nuclear non-coding RNAs to respond to DNA damage. Our findings highlight that the structure switch of the CTD induced by posttranslational modifications redefines the subset of binding partners, and thereby the RNA targets in the nucleoli. View Full-Text
Keywords: DNA damage response; function switch; intrinsically disordered domain; nucleolar localization; phosphorylation; poly(A)-specific ribonuclease (PARN); RNA maturation; structure switch DNA damage response; function switch; intrinsically disordered domain; nucleolar localization; phosphorylation; poly(A)-specific ribonuclease (PARN); RNA maturation; structure switch
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MDPI and ACS Style

Duan, T.-L.; He, G.-J.; Hu, L.-D.; Yan, Y.-B. The Intrinsically Disordered C-Terminal Domain Triggers Nucleolar Localization and Function Switch of PARN in Response to DNA Damage. Cells 2019, 8, 836.

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