A potent nuclear export mechanism imposes USP16 cytoplasmic localization during interphase.

Cell proliferation; DNA double-strand break repair; Deubiquitylase; H2AK119; Mitosis; Nuclear export; UBP-M; USP16; Ubiquitin; Nuclear Export Signals; Nuclear Localization Signals; Active Transport, Cell Nucleus; Cytoplasm/genetics; Cytoplasm/metabolism; Interphase; Nuclear Localization Signals/genetics; Nuclear Localization Signals/metabolism; Cell Nucleus/genetics; Cell Nucleus/metabolism; Nuclear Export Signals/genetics; Cell Nucleus; Cytoplasm; Cell Biology

Abstract :

[en] USP16 (also known as UBP-M) has emerged as a histone H2AK119 deubiquitylase (DUB) implicated in the regulation of chromatin-associated processes and cell cycle progression. Despite this, available evidence suggests that this DUB is also present in the cytoplasm. How the nucleo-cytoplasmic transport of USP16, and hence its function, is regulated has remained elusive. Here, we show that USP16 is predominantly cytoplasmic in all cell cycle phases. We identified the nuclear export signal (NES) responsible for maintaining USP16 in the cytoplasm. We found that USP16 is only transiently retained in the nucleus following mitosis and then rapidly exported from this compartment. We also defined a non-canonical nuclear localization signal (NLS) sequence that plays a minimal role in directing USP16 into the nucleus. We further established that this DUB does not accumulate in the nucleus following DNA damage. Instead, only enforced nuclear localization of USP16 abolishes DNA double-strand break (DSB) repair, possibly due to unrestrained DUB activity. Thus, in contrast to the prevailing view, our data indicate that USP16 is actively excluded from the nucleus and that this DUB might indirectly regulate DSB repair.This article has an associated First Person interview with the first author of the paper.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Sen Nkwe, Nadine ; Maisonneuve-Rosemont Hospital Research Center, Montréal, QC H1T 2M4, Canada

Daou, Salima ; Maisonneuve-Rosemont Hospital Research Center, Montréal, QC H1T 2M4, Canada ; Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada

Uriarte, Maxime ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques ; Maisonneuve-Rosemont Hospital Research Center, Montréal, QC H1T 2M4, Canada

Gagnon, Jessica ; Maisonneuve-Rosemont Hospital Research Center, Montréal, QC H1T 2M4, Canada ; Institute for Research in Immunology and Cancer, University of Montréal, Montréal, QC H3T 1J4, Canada

Iannantuono, Nicholas Victor ; Maisonneuve-Rosemont Hospital Research Center, Montréal, QC H1T 2M4, Canada ; Institute for Research in Immunology and Cancer, University of Montréal, Montréal, QC H3T 1J4, Canada

Barbour, Haithem ; Maisonneuve-Rosemont Hospital Research Center, Montréal, QC H1T 2M4, Canada

Yu, Helen ; Maisonneuve-Rosemont Hospital Research Center, Montréal, QC H1T 2M4, Canada ; Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada

Masclef, Louis ; Maisonneuve-Rosemont Hospital Research Center, Montréal, QC H1T 2M4, Canada

Fernández, Erlinda ; Maisonneuve-Rosemont Hospital Research Center, Montréal, QC H1T 2M4, Canada

Zamorano Cuervo, Natalia ; Maisonneuve-Rosemont Hospital Research Center, Montréal, QC H1T 2M4, Canada ; CRCHUM-Centre Hospitalier de l'Université de Montréal, 900 rue Saint Denis, Montréal, QC H2X 0A9, Canada

More authors (9 more)

Language :

English

Title :

A potent nuclear export mechanism imposes USP16 cytoplasmic localization during interphase.

Publication date :

24 February 2020

Journal title :

Journal of Cell Science

ISSN :

0021-9533

eISSN :

1477-9137

Publisher :

Company of Biologists Ltd, England

Volume :

133

Issue :

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://syndication.highwire.org/content/doi/10.1242/jcs.239236

Funders :

NSERC - Natural Sciences and Engineering Research Council
FRQS - Fonds de Recherche du Québec - Santé
FRQNT - Fonds de Recherche du Québec - Nature et Technologies

Funding text :

This work was supported by a discovery grant (2015-2021) to E.B.A. from The Natural Sciences and Engineering Research Council of Canada (NSERC), a discovery grant (2013-2019) to H.W. from NSERC, a discovery grant (2018-2023) to E.M. from NSERC and a discovery grant (2016-2021) to S.C. from NSERC. H.W., S.C. and E.B.A. are Scholars of Fonds de la Recherche du Québec en Santé (FRQ-S). J.G. was supported by a Master’s scholarship from the FRQ-S. N.S.N. was supported by a PhD scholarship from the FRQ-S. N.M. was supported by a PhD scholarship from Fonds de Recherche du Québec-Nature et Technologies (FRQ-NT). H.Y. was supported by a PhD scholarship from the CIHR.

Available on ORBi :

since 27 December 2024

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