USP15 deubiquitinase safeguards hematopoiesis and genome integrity in hematopoietic stem cells and leukemia cells

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Item Type:

Article

Title:

USP15 deubiquitinase safeguards hematopoiesis and genome integrity in hematopoietic stem cells and leukemia cells

Creators Name:

van den Berk, P. and Lancini, C. and Company, C. and Serresi, M. and Sanchez-Bailon, M.P. and Hulsman, D. and Pritchard, C. and Song, J.Y. and Schmitt, M.J. and Tanger, E. and Popp, O. and Mertins, P. and Huijbers, I.J. and Jacobs, H. and van Lohuizen, M. and Gargiulo, G. and Citterio, E.

Abstract:

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:

Hematopoietic Stem Cell, HSC, USP15, Deubiquitinating Enzymes, Deubiquitinase, In vivo shRNA Screen, Leukemia, DNA Damage Response, Genome Integrity, FUS, Fused in Sarcoma, RNAi, Animals, Mice, Inbred C57BL Mice, Knockout Mice

Source:

Cell Reports

ISSN:

2211-1247

Publisher:

Cell Press / Elsevier

Volume:

Number:

Page Range:

108533

Date:

29 December 2020