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

Cells
Tian-Li DuanYong-Bin Yan

Abstract

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-co...Continue Reading

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Citations

Nov 12, 2019·Protein Science : a Publication of the Protein Society·Stuart A MacGowanGeoffrey J Barton
Feb 29, 2020·Cells·Ursula Stochaj, Stephanie C Weber
Aug 14, 2020·Wiley Interdisciplinary Reviews. RNA·Yong-Bin Yan
Sep 3, 2020·Genes & Development·Xavier Rambout, Lynne E Maquat
May 28, 2020·The Journal of Biological Chemistry·Eden A DejeneEdward Seto

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Methods Mentioned

BETA
transfection
circular dichroism
Assay
PCR
flow cytometry
Co-IP
pull down
confocal microscopy

Software Mentioned

PARN
CDpro
GraphPad Prism
GraphPad
CTD
NoD
PORT

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