Tight regulation of ubiquitin-mediated DNA damage response by USP3 preserves the functional integrity of hematopoietic stem cells
Cesare Lancini, Paul CM van den Berk, Joseph HA Vissers, Gaetano Gargiulo, Ji-Ying Song, Danielle Hulsman, Michela Serresi, Ellen Tanger, Marleen Blom, Conchita Vens, Maarten van Lohuizen, Heinz Jacobs, Elisabetta Citterio
Journal of Experimental Medicine | ROCKEFELLER UNIV PRESS | Published : 2014
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 sel..View full abstract
Awarded by Dutch Cancer Society (KWF)
Awarded by Dutch Organization for Scientific Research NWO Vidi
This work was supported by the Dutch Cancer Society (KWF) to E. Citterio and M. van Lohuizen (NKI-2007-3877 and NKI-2012-5665), to G. Gargiulo and M. van Lohuizen (NKI 2013-6030), and to H. Jacobs (NKI-2008-4112 and NKI-2012-5243), and by the Dutch Organization for Scientific Research NWO Vidi to E. Citterio (864.08.011).