The CUL4-DDB1 ubiquitin ligase complex controls adult and embryonic stem cell differentiation and homeostasis

  • Gao J
  • Buckley S
  • Cimmino L
  • et al.
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Abstract

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.Stem cells can develop into other types of cells via a process called “differentiation”. When a stem cell divides in two, it typically produces another stem cell and a cell that goes on to differentiate. Hematopoietic stem cells (or HSCs) are found in the bone marrow and give rise to all blood cells throughout the life of an organism. It is therefore crucial that they divide correctly to maintain the balance between renewing their numbers and making new types of cells.Many studies have investigated how stem cells are maintained, but there are still major gaps in our knowledge. Recent research suggested that the cell’s “ubiquitin-proteasome system” might be important for regulating stem cell division. This system rapidly degrades proteins, thereby regulating protein abundance in cells. Enzymes known as E3 ligases form part of this system, and recognize proteins to be marked for destruction with a small protein tag.Gao et al. have now observed that a component of an E3 ligase called DDB1 is highly expressed in hematopoietic stem cells. Further experiments revealed that genetically engineered mice that lack DDB1 in their population of blood cells die soon after they are born and have fewer blood cells. Gao et al. next inhibited the production of DDB1 in adult mice. This stopped the adult mice’s hematopoietic stem cells from dividing, and the mice died because their bone marrow couldn’t produce new blood cells. These results show that DDB1 is necessary for stem cells to renew their numbers and differentiate into blood cells in both developing and adult animals.Next, Gao et al. investigated the how DDB1 regulates stem cell division, and discovered that a protein called p53, which is a key player in controlling cell division, is regulated by DDB1. Under normal conditions, p53 levels are kept low in cells. However, in the absence of DDB1, the levels of p53 rise, which triggers the death of the hematopoietic stem cells.Further experiments revealed that not all dividing cells undergo cell death with the loss of DDB1. Instead, Gao et al. found that rapidly dividing embryonic stem cells differentiate when DDB1 is lost but do not die. These findings suggest that specific components of the ubiquitin ligase complex play a key role in deciding a stem cell’s fate. In the future, identifying these components will further our understanding of the decision of stem cells to differentiate.

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Gao, J., Buckley, S. M., Cimmino, L., Guillamot, M., Strikoudis, A., Cang, Y., … Aifantis, I. (2015). The CUL4-DDB1 ubiquitin ligase complex controls adult and embryonic stem cell differentiation and homeostasis. ELife, 4. https://doi.org/10.7554/elife.07539

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