[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
Mashtalir, Nazar ; Maisonneuve-Rosemont Hospital Research Center, Montréal, QC H1T 2M4, Canada ; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA ; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Binan, Loïc ; Maisonneuve-Rosemont Hospital Research Center, Montréal, QC H1T 2M4, Canada ; Department of Ophthalmology, University of Montréal, Montréal, Québec, Canada
Sergeev, Mikhail ; Maisonneuve-Rosemont Hospital Research Center, Montréal, QC H1T 2M4, Canada
Bélanger, François ; Maisonneuve-Rosemont Hospital Research Center, Montréal, QC H1T 2M4, Canada
Drobetsky, Elliot ; Maisonneuve-Rosemont Hospital Research Center, Montréal, QC H1T 2M4, Canada ; Department of Medicine, University of Montréal, Montréal H3C 3J7, Québec, Canada
Milot, Eric ; Maisonneuve-Rosemont Hospital Research Center, Montréal, QC H1T 2M4, Canada ; Department of Medicine, University of Montréal, Montréal H3C 3J7, Québec, Canada
Wurtele, Hugo ; Maisonneuve-Rosemont Hospital Research Center, Montréal, QC H1T 2M4, Canada ; Department of Medicine, University of Montréal, Montréal H3C 3J7, Québec, Canada
Costantino, Santiago ; Maisonneuve-Rosemont Hospital Research Center, Montréal, QC H1T 2M4, Canada ; Department of Ophthalmology, University of Montréal, Montréal, Québec, Canada
Affar, El Bachir ; Maisonneuve-Rosemont Hospital Research Center, Montréal, QC H1T 2M4, Canada el.bachir.affar@umontreal.ca ; Department of Medicine, University of Montréal, Montréal H3C 3J7, Québec, Canada
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.
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