PubMed · 20043
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P Mitchell. 1977. Vectorial chemiosmotic processes.. https://doi.org/10.1146/annurev.bi.46.070177.005024
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PURPOSE: Diphthamide is a post-translationally modified histidine essential for messenger RNA translation and ribosomal protein synthesis. We present evidence for DPH5 as a novel cause of embryonic lethality and profound neurodevelopmental delays (NDDs). METHODS: Molecular testing was performed using exome or genome sequencing. A targeted Dph5 knockin mouse (C57BL/6Ncrl-Dph5em1Mbp/Mmucd) was created for a DPH5 p.His260Arg homozygous variant identified in 1 family. Adenosine diphosphate-ribosylation assays in DPH5-knockout human and yeast cells and in silico modeling were performed for the identified DPH5 potential pathogenic variants. RESULTS: DPH5 variants p.His260Arg (homozygous), p.Asn110Ser and p.Arg207Ter (heterozygous), and p.Asn174LysfsTer10 (homozygous) were identified in 3 unrelated families with distinct overlapping craniofacial features, profound NDDs, multisystem abnormalities, and miscarriages. Dph5 p.His260Arg homozygous knockin was embryonically lethal with only 1 subviable mouse exhibiting impaired growth, craniofacial dysmorphology, and multisystem dysfunction recapitulating the human phenotype. Adenosine diphosphate-ribosylation assays showed absent to decreased function in DPH5-knockout human and yeast cells. In silico modeling of the variants showed altered DPH5 structure and disruption of its interaction with eEF2. CONCLUSION: We provide strong clinical, biochemical, and functional evidence for DPH5 as a novel cause of embryonic lethality or profound NDDs with multisystem involvement and expand diphthamide-deficiency syndromes and ribosomopathies.
There are a wide variety of helicases that unwind helical DNA and RNA substrates. The twelve helicases that have been identified in Escherichia coli play a role in almost all cellular processes involving nucleic acids. We have solved the crystal structure of a monomeric form of a DNA helicase from Bacillus stearothermophilus, alone and in a complex with ADP, at 2.5 and 2.9 A resolution, respectively. The enzyme comprises two domains with a deep cleft running between them. The ATP-binding site, which is situated at the bottom of this cleft, is formed by motifs that are conserved across the superfamily of related helicases. Unexpected structural homology with the DNA recombination protein, RecA, suggests how ATP binding and hydrolysis may drive conformational changes of the enzyme during catalysis, and implies that there is a common mechanism for all helicases.
Cytotoxic mechanisms of the antitumor agents daunorubicin and doxorubicin were elucidated in isolated cardiomyocytes from adult rats. Incubation with daunorubicin resulted in a concentration-dependent loss of cell viability and changes of the cell structure. Only the highest concentration of doxorubicin (1 mM) caused similar effects. Doxorubicin was found to stimulate oxygen consumption by cardiomyocytes (about 20%), while the opposite effect was observed after daunorubicin treatment. A rapid decrease of the mitochondrial ATP content (more than 40%) and elevation of the cytosolic ADP level (doxorubicin 2-fold and daunorubicin 6-fold) was followed by increased release of adenosine and inosine to the surrounding medium. When myocytes were exposed to an anthracycline concentration lower than plasma levels measured clinically (0.15 microM), doxorubicin and daunorubicin significantly decreased the intracellular ADP and NAD levels. Isolated cardiomyocytes were found to be able to form daunorubicinol from daunorubicin. In contrast, no conversion of doxorubicin was detected in our experiments. In conclusion, our data demonstrate that decreased ATP production and increased nucleoside formation are major events in the toxicity induced by daunorubicin and doxorubicin in isolated cardiomyocytes. The results also suggest that the toxic effects may be caused by separate mechanisms.