title: Tight regulation of ubiquitin-mediated DNA damage response by USP3 preserves the functional integrity of hematopoietic stem cells.
abstract: Histone ubiquitination at DNA breaks is required for activation of the DNA damage response (DDR) and DNA repair. How the dynamic removal of this modification by deubiquitinating enzymes (DUBs) impacts genome maintenance in vivo is largely unknown. To address this question, we generated mice deficient for Ub-specific protease 3 (USP3; Usp3Δ/Δ), a histone H2A DUB which negatively regulates ubiquitin-dependent DDR signaling. Notably, USP3 deletion increased the levels of histone ubiquitination in adult tissues, reduced the hematopoietic stem cell (HSC) reserves over time, and shortened animal life span. Mechanistically, our data show that USP3 is important in HSC homeostasis, preserving HSC self-renewal, and repopulation potential in vivo and proliferation in vitro. A defective DDR and unresolved spontaneous DNA damage contribute to cell cycle restriction of Usp3Δ/Δ HSCs. Beyond the hematopoietic system, Usp3Δ/Δ animals spontaneously developed tumors, and primary Usp3Δ/Δ cells failed to preserve chromosomal integrity. These findings broadly support the regulation of chromatin ubiquitination as a key pathway in preserving tissue function through modulation of the response to genotoxic stress.
authors.affiliation: Division of Molecular Genetics, Division of Biological Stress Response, and Division of Experimental Animal Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
authors.forename: Cesare
authors.initials: C
authors.lastname: Lancini
authors.affiliation: Division of Molecular Genetics, Division of Biological Stress Response, and Division of Experimental Animal Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
authors.forename: Paul C M
authors.initials: PC
authors.lastname: van den Berk
authors.affiliation: Division of Molecular Genetics, Division of Biological Stress Response, and Division of Experimental Animal Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
authors.forename: Joseph H A
authors.initials: JH
authors.lastname: Vissers
authors.affiliation: Division of Molecular Genetics, Division of Biological Stress Response, and Division of Experimental Animal Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Gargiulo
authors.affiliation: Division of Molecular Genetics, Division of Biological Stress Response, and Division of Experimental Animal Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
authors.forename: Ji-Ying
authors.initials: JY
authors.lastname: Song
authors.affiliation: Division of Molecular Genetics, Division of Biological Stress Response, and Division of Experimental Animal Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
authors.forename: Danielle
authors.initials: D
authors.lastname: Hulsman
authors.affiliation: Division of Molecular Genetics, Division of Biological Stress Response, and Division of Experimental Animal Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
authors.forename: Michela
authors.initials: M
authors.lastname: Serresi
authors.affiliation: Division of Molecular Genetics, Division of Biological Stress Response, and Division of Experimental Animal Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: Tanger
authors.affiliation: Division of Molecular Genetics, Division of Biological Stress Response, and Division of Experimental Animal Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
authors.forename: Marleen
authors.initials: M
authors.lastname: Blom
authors.affiliation: Division of Molecular Genetics, Division of Biological Stress Response, and Division of Experimental Animal Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
authors.forename: Conchita
authors.initials: C
authors.lastname: Vens
authors.affiliation: Division of Molecular Genetics, Division of Biological Stress Response, and Division of Experimental Animal Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: van Lohuizen
authors.affiliation: Division of Molecular Genetics, Division of Biological Stress Response, and Division of Experimental Animal Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
authors.forename: Heinz
authors.initials: H
authors.lastname: Jacobs
authors.affiliation: Division of Molecular Genetics, Division of Biological Stress Response, and Division of Experimental Animal Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands e.citterio@nki.nl.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Citterio
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D049109:Cell Proliferation; D016922:Cellular Senescence; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006706:Homeostasis; D008231:Lymphopenia / Q000209:etiology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064570:Ubiquitin-Specific Proteases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D006657:Histones; C000592507:USP3 protein, mouse; D064570:Ubiquitin-Specific Proteases
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