The Ribosome Biogenesis Protein Nol9 Is Essential for Definitive Hematopoiesis and Pancreas Morphogenesis in Zebrafish

RAD51 is an indispensable homologous recombination protein, necessary for strand invasion and crossing over. It has recently been designated as a Fanconi anemia (FA) gene, following the discovery of two patients carrying dominant-negative mutations. FA is a hereditary DNA-repair disorder characterized by various congenital abnormalities, progressive bone marrow failure, and cancer predisposition. In this report, we describe a viable vertebrate model of loss. Zebrafish loss-of-function mutants developed key features of FA, including hypocellular kidney marrow, sensitivity to cross-linking agents, and decreased size. We show that some of these symptoms stem from both decreased proliferation and increased apoptosis of embryonic hematopoietic stem and progenitor cells. Comutation of was able to rescue the hematopoietic defects seen in the single mutants, but led to tumor development. We further demonstrate that prolonged inflammatory stress can exacerbate the hematological impairment, leading to an additional decrease in kidney marrow cell numbers. These findings strengthen the assignment of as a Fanconi gene and provide more evidence for the notion that aberrant p53 signaling during embryogenesis leads to the hematological defects seen later in life in FA. Further research on this zebrafish FA model will lead to a deeper understanding of the molecular basis of bone marrow failure in FA and the cellular role of RAD51.

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“…Western Blotting. Western blotting was carried out as described previously (67). Antibodies can be found in SI Appendix, Table S1.…”

Section: Methodsmentioning

confidence: 99%

Loss of the homologous recombination gene rad51 leads to Fanconi anemia-like symptoms in zebrafish

Botthof

Bielczyk-Maczyńska

Ferreira

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Western blotting was carried out as described previously (67). Antibodies can be found in SI Appendix, Table S1.…”

Section: Methodsmentioning

confidence: 99%

Loss of the homologous recombination generad51leads to Fanconi anemia-like symptoms in zebrafish

Botthof

Bielczyk-Maczyńska

Ferreira

et al. 2016

Preprint

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RAD51 is an indispensable homologous recombination protein, necessary for strand invasion and crossing over. It has recently been designated as a Fanconi anemia (FA) gene, following the discovery of two patients carrying dominant-negative mutations. FA is a hereditary DNA-repair disorder characterized by various congenital abnormalities, progressive bone marrow failure, and cancer predisposition. In this report, we describe a viable vertebrate model of RAD51 loss. Zebrafish rad51 loss-of-function mutants developed key features of FA, including hypocellular kidney marrow, sensitivity to cross-linking agents, and decreased size. We show that some of these symptoms stem from both decreased proliferation and increased apoptosis of embryonic hematopoietic stem and progenitor cells. Comutation of p53 was able to rescue the hematopoietic defects seen in the single mutants, but led to tumor development. We further demonstrate that prolonged inflammatory stress can exacerbate the hematological impairment, leading to an additional decrease in kidney marrow cell numbers. These findings strengthen the assignment of RAD51 as a Fanconi gene and provide more evidence for the notion that aberrant p53 signaling during embryogenesis leads to the hematological defects seen later in life in FA. Further research on this zebrafish FA model will lead to a deeper understanding of the molecular basis of bone marrow failure in FA and the cellular role of RAD51.

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“…This pool is carefully regulated by ribosome biogenesis and is adjustable to cellular needs 15 – 17 . Because 'free' ribosome availability is a limiting parameter in the process of translation 18 , any quantitative change in ribosome homeostasis may impact translation process 19 , 20 . First, mRNAs with low translation initiation rates are more 'sensitive' to variations in ribosome numbers in comparison with highly translated mRNAs 21 .…”

Section: The Revisited Ribosomementioning

confidence: 99%

The ribosome, (slow) beating heart of cancer (stem) cell

Bastide

David

2018

Oncogenesis

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The ribosome has long been considered as a consistent molecular factory, with a rather passive role in the translation process. Recent findings have shifted this obsolete view, revealing a remarkably complex and multifaceted machinery whose role is to orchestrate spatiotemporal control of gene expression. Ribosome specialization discovery has raised the interesting possibility of the existence of its malignant counterpart, an 'oncogenic' ribosome, which may promote tumor progression. Here we weigh the arguments supporting the existence of an 'oncogenic' ribosome and evaluate its role in cancer evolution. In particular, we provide an analysis and perspective on how the ribosome may play a critical role in the acquisition and maintenance of cancer stem cell phenotype.

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The Ribosome Biogenesis Protein Nol9 Is Essential for Definitive Hematopoiesis and Pancreas Morphogenesis in Zebrafish

Cited by 26 publications

References 89 publications

Loss of the homologous recombination gene rad51 leads to Fanconi anemia-like symptoms in zebrafish

Loss of the homologous recombination gene rad51 leads to Fanconi anemia-like symptoms in zebrafish

Loss of the homologous recombination generad51leads to Fanconi anemia-like symptoms in zebrafish

The ribosome, (slow) beating heart of cancer (stem) cell

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