1. Stem Cells and Regenerative Medicine
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The CUL4-DDB1 ubiquitin ligase complex controls adult and embryonic stem cell differentiation and homeostasis

  1. Jie Gao
  2. Shannon M Buckley
  3. Luisa Cimmino
  4. Maria Guillamot
  5. Alexandros Strikoudis
  6. Yong Cang
  7. Stephen P Goff
  8. Iannis Aifantis  Is a corresponding author
  1. New York University School of Medicine, United States
  2. Sanford-Burnham Medical Research Institute, United States
  3. Howard Hughes Medical Institute, Columbia University, United States
Research Article
  • Cited 11
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Cite this article as: eLife 2015;4:e07539 doi: 10.7554/eLife.07539

Abstract

Little is known on post-transcriptional regulation of stem cell maintenance and differentiation. Here we characterize the role of Ddb1, a component of the CUL4-DDB1 ligase complex. Ddb1 is highly expressed in hematopoietic stem cells and its deletion leads to abrogation of hematopoiesis, targeting specifically transiently amplifying progenitor subsets. Ddb1 deletion in non-dividing lymphocytes had no discernible phenotypes. Ddb1 silencing activated the p53 pathway and lead to apoptosis. The abrogation of hematopoietic progenitor cells can be partially rescued by simultaneous deletion of p53. Interestingly, depletion of DDB1 in embryonic stem cell (ESC) does not affect survival or cell cycle progression but leads to loss of pluripotency, suggesting distinct roles of DDB1 in adult and embryonic stem cells. Mass-spectrometry revealed distinct interactions between DDB1 and DCAFs, the substrate-recognizing components of the CUL4 complex between cell types. Our studies identify the CUL4-DDB1 complex as a novel post-translational regulator of stem maintenance and differentiation.

Article and author information

Author details

  1. Jie Gao

    Department of Pathology and Perlmutter Cancer Center, New York University School of Medicine, New York, United States
    Competing interests
    No competing interests declared.
  2. Shannon M Buckley

    Department of Pathology and Perlmutter Cancer Center, New York University School of Medicine, New York, United States
    Competing interests
    No competing interests declared.
  3. Luisa Cimmino

    Department of Pathology and Perlmutter Cancer Center, New York University School of Medicine, New York, United States
    Competing interests
    No competing interests declared.
  4. Maria Guillamot

    Department of Pathology and Perlmutter Cancer Center, New York University School of Medicine, New York, United States
    Competing interests
    No competing interests declared.
  5. Alexandros Strikoudis

    Department of Pathology and Perlmutter Cancer Center, New York University School of Medicine, New York, United States
    Competing interests
    No competing interests declared.
  6. Yong Cang

    Signal Transduction Program, Sanford-Burnham Medical Research Institute, La Jolla, United States
    Competing interests
    No competing interests declared.
  7. Stephen P Goff

    Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, Columbia University, New York, United States
    Competing interests
    Stephen P Goff, Reviewing editor, eLife.
  8. Iannis Aifantis

    Department of Pathology and Perlmutter Cancer Center, New York University School of Medicine, New York, United States
    For correspondence
    iannis.aifantis@nyumc.org
    Competing interests
    No competing interests declared.

Ethics

Animal experimentation: All animal experiments were done in accordance to the guidelines of the NYU School of Medicine, and approved by the institutional animal care and use committee (IACUC) protocol (#130410-03).

Reviewing Editor

  1. Amy J Wagers, Harvard University, United States

Publication history

  1. Received: March 17, 2015
  2. Accepted: November 26, 2015
  3. Accepted Manuscript published: November 27, 2015 (version 1)
  4. Version of Record published: January 6, 2016 (version 2)

Copyright

© 2015, Gao et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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