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Tight regulation of ubiquitin-mediated DNA damage response by USP3 preserves the functional integrity of hematopoietic stem cells

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Item Type:Article
Title:Tight regulation of ubiquitin-mediated DNA damage response by USP3 preserves the functional integrity of hematopoietic stem cells
Creators Name:Lancini, C. and van den Berk, P.C.M. and Vissers, J.H.A. and Gargiulo, G. and Song, J.Y. and Hulsman, D. and Serresi, M. and Tanger, E. and Blom, M. and Vens, C. and van Lohuizen, M. and Jacobs, H. and Citterio, E.
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; Usp3{delta}/{delta}), 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 Usp3{delta}/{delta} HSCs. Beyond the hematopoietic system, Usp3{delta}/{delta} animals spontaneously developed tumors, and primary Usp3{delta}/{delta} 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.
Keywords:129 Strain Mice, Carcinogenesis, Cell Aging, Cell Proliferation, DNA Damage, DNA Repair, Double-Stranded DNA Breaks, Hematopoietic Stem Cells, Histones, Homeostasis, Inbred C57BL Mice, Knockout Mice, Lymphopenia, Ubiquitin-Specific Proteases, Ubiquitination, Animals, Mice
Source:Journal of Experimental Medicine
ISSN:0022-1007
Publisher:Rockefeller University Press (U.S.A.)
Volume:211
Number:9
Page Range:1759-1777
Date:25 August 2014
Official Publication:https://doi.org/10.1084/jem.20131436
PubMed:View item in PubMed

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