The CUL4-DDB1 ubiquitin ligase complex controls adult and embryonic stem cell differentiation and homeostasis
Jie Gao,
Shannon M Buckley,
Luisa Cimmino,
Maria Guillamot,
Alexandros Strikoudis,
Yong Cang,
Stephen P Goff,
Iannis Aifantis
Affiliations
Jie Gao
Department of Pathology, New York University School of Medicine, New York, United States; Perlmutter Cancer Center, New York University School of Medicine, New York, United States
Shannon M Buckley
Department of Pathology, New York University School of Medicine, New York, United States; Perlmutter Cancer Center, New York University School of Medicine, New York, United States; Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, United States
Luisa Cimmino
Department of Pathology, New York University School of Medicine, New York, United States; Perlmutter Cancer Center, New York University School of Medicine, New York, United States
Maria Guillamot
Department of Pathology, New York University School of Medicine, New York, United States; Perlmutter Cancer Center, New York University School of Medicine, New York, United States
Alexandros Strikoudis
Department of Pathology, New York University School of Medicine, New York, United States; Perlmutter Cancer Center, New York University School of Medicine, New York, United States
Yong Cang
Signal Transduction Program, Sanford-Burnham Medical Research Institute, La Jolla, United States
Stephen P Goff
Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, Columbia University, New York, United States
Iannis Aifantis
Department of Pathology, New York University School of Medicine, New York, United States; Perlmutter Cancer Center, New York University School of Medicine, New York, United States
Little is known on post-transcriptional regulation of adult and embryonic stem cell maintenance and differentiation. Here we characterize the role of Ddb1, a component of the CUL4-DDB1 ubiquitin ligase complex. Ddb1 is highly expressed in multipotent hematopoietic progenitors and its deletion leads to abrogation of both adult and fetal hematopoiesis, targeting specifically transiently amplifying progenitor subsets. However, Ddb1 deletion in non-dividing lymphocytes has no discernible phenotypes. Ddb1 silencing activates Trp53 pathway and leads to significant effects on cell cycle progression and rapid apoptosis. The abrogation of hematopoietic progenitor cells can be partially rescued by simultaneous deletion of Trp53. Conversely, depletion of DDB1 in embryonic stem cell (ESC) leads to differentiation albeit negative effects on cell cycle and apoptosis. Mass spectrometry reveals differing protein interactions between DDB1 and distinct DCAFs, the substrate recognizing components of the E3 complex, between cell types. Our studies identify CUL4-DDB1 complex as a novel post-translational regulator of stem and progenitor maintenance and differentiation.
