The CUL4-DDB1 ubiquitin ligase complex controls adult and embryonic stem cell differentiation and homeostasis
- New York University School of Medicine, United States
- Sanford-Burnham Medical Research Institute, United States
- Howard Hughes Medical Institute, Columbia University, United States
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.
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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).
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© 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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The CUL4-DDB1 ubiquitin ligase complex controls adult and embryonic stem cell differentiation and homeostasis
eLife 4:e07539.
https://doi.org/10.7554/eLife.07539
