USP15 Deubiquitinase Safeguards Hematopoiesis and Genome Integrity in Hematopoietic Stem Cells and Leukemia Cells

Cell Rep. 2020 Dec 29;33(13):108533. doi: 10.1016/j.celrep.2020.108533.


Altering ubiquitination by disruption of deubiquitinating enzymes (DUBs) affects hematopoietic stem cell (HSC) maintenance. However, comprehensive knowledge of DUB function during hematopoiesis in vivo is lacking. Here, we systematically inactivate DUBs in mouse hematopoietic progenitors using in vivo small hairpin RNA (shRNA) screens. We find that multiple DUBs may be individually required for hematopoiesis and identify ubiquitin-specific protease 15 (USP15) as essential for HSC maintenance in vitro and in transplantations and Usp15 knockout (KO) mice in vivo. USP15 is highly expressed in human hematopoietic tissues and leukemias. USP15 depletion in murine progenitors and leukemia cells impairs in vitro expansion and increases genotoxic stress. In leukemia cells, USP15 interacts with and stabilizes FUS (fused in sarcoma), a known DNA repair factor, directly linking USP15 to the DNA damage response (DDR). Our study underscores the importance of DUBs in preserving normal hematopoiesis and uncovers USP15 as a critical DUB in safeguarding genome integrity in HSCs and leukemia cells.

Keywords: DNA damage response; FUS; HSC; RNAi; USP15; deubiquitinase; deubiquitinating enzymes; fused in sarcoma; genome integrity; hematopoietic stem cell; in vivo shRNA screen; leukemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Proliferation
  • DNA Damage
  • DNA Repair
  • Deubiquitinating Enzymes / physiology*
  • Hematopoiesis
  • Hematopoietic Stem Cells / enzymology
  • Hematopoietic Stem Cells / physiology*
  • Humans
  • K562 Cells
  • Leukemia / enzymology
  • Leukemia / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Animal
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • RNA-Binding Protein FUS / metabolism*
  • Ubiquitin-Specific Proteases / physiology*
  • Ubiquitination


  • FUS protein, human
  • RNA, Small Interfering
  • RNA-Binding Protein FUS
  • Deubiquitinating Enzymes
  • USP15 protein, human
  • Ubiquitin-Specific Proteases
  • Usp15 protein, mouse