The results enhance our understanding of the importance of ribosome assembly in stem cell regeneration and potential therapeutic strategies for ribosomal impairments, which lead to bone marrow abnormalities in children.
Philadelphia, March 11, 2021 – Researchers at Children’s Hospital of Philadelphia (CHOP) have identified genes responsible for regenerating hematopoietic stem cells (HSC) by assembling ribosomes, protein factories in cells that translate the mRNA sequence into an amino acid sequence. The results were published in Stem cell cells, Highlighting the importance of correct ribosome assembly in stem cell regeneration and identifying potential targets for future therapies for ribosomal impairment and childhood disorders that lead to bone marrow failure (BMF).
Said Wei Tong, Ph.D., researcher and professor of pediatric hematology at CHOP Hospital and senior author of the paper. “This study identified a mechanism that prevents ribosomes from assembling properly in mammals, leading to insufficient hematopoietic stem cells, which could be exploited in future therapeutic interventions.”
Ribosomal disorders describe a group of inherited biomagnification factor syndromes with impaired ribosome function. Individuals with ribosomal impairment have a deficiency of cancer stem cells but are also at increased risk of developing leukemia and cancer. Schwachmann-Diamond syndrome (SDS), a rare blood disorder that affects the pancreas, bone marrow and skeleton, is an example of biomagnification factor syndrome associated with ribosome defect caused by mutations of ribosome-aggregating factors. Understanding how ribosomal abnormalities lead to biomagnification and predisposition to cancer is essential in developing treatments for these disorders, but prior to this study, researchers had little evidence of how the assembly factors themselves were regulated and how they affected hematopoietic regeneration in mammals.
Working in a rat model, the researchers identified E3 ubiquitin ligase HectD1 as playing a key role in regulating HSC function via ribosome assembly and protein translation. Assembling the ribosome involves bringing in a large subunit with a small subunit for translating mRNA into proteins. Aggregators help with this process, including one called ZNF622 in the large subunit. In HSCs under stress conditions, such as inflammation or injury, HectD1 marks ZNF622 for destruction, allowing ribosome assembly to occur. However, cells lacking the Hectd1 gene accumulate ZNF622 because they are no longer labeled for destruction, preventing large and small subunits from joining.
The researchers also found that shedding the Znf622 gene in Hectd1-deficient cancer stem cells restored the ability of large and small subunits to join properly, resulting in the restoration of protein synthesis and HSC production.
“These results not only highlight the relationship between protein degradation, ribosome aggregation, and stem cell production, but also reveal the potential for Znf622 catabolism to restore adequate bone marrow function, which is critical for a child’s development,” said Tong. “Future research should look at this mechanism as a potential target for patients with these disorders.”
Funding for this work was provided by the National Institutes of Health, the Department of Defense, the St. Baldrake Foundation, the Alex Lemonade Research Foundation, and the Basser BRCA Research Center, among others.
Kaosheng Lv et al. “HectD1 controls regeneration of hematopoietic stem cells by coordinating ribosome assembly and protein synthesis,” Stem cell cells, Online March 11, 2021, DOI: 10.1016 / j.stem.2021.02.008
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