PubMed · 6049350
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N Tanaka, H Masukawa, H Umezawa. 1967-03-09. Structural basis of kanamycin for miscoding activity.. https://doi.org/10.1016/0006-291x(67)90099-x
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RNase L is responsible for the 2-5A host defense system, an RNA degradation pathway present in cells of higher vertebrates that functions in both the antiviral and anticellular activities of interferon. The activity of RNase L is tightly regulated and is exerted only in the presence of 2-5A. The postulated mechanism of its regulation is as follows: the N-terminal half ankyrin-repeat domain masks the C-terminal half nuclease domain in the absence of 2-5A. On binding 2-5A at the ankyrin-repeat domain, RNase L forms a homodimer and removes the ankyrin-repeat domain from the nuclease domain to become the active form. A conformational change in the ankyrin-repeat domain is a key step in this hypothetical mechanism, but there is as yet no evidence for such a change. To clarify the events induced by 2-5A binding, we established procedures for expression and purification of the ankyrin-repeat domain of human RNase L. Fluorescence spectra of the protein showed clear difference in the presence and absence of 2-5A. The alterations in the spectra supported conformational changes of the protein. Time-resolved anisotropy measurements indicated that 2-5A binding led to a significant decrease in the rotational radius of the protein. In addition, 2-5A provided the domain with resistance to protease digestion as a result of a conformational change. These results indicated that the ankyrin-repeat domain of RNase L constricts its structure by binding of 2-5A. This observation suggests a revised model of the 2-5A-induced activation of RNase L.
DNA polymerase (pol) eta participates in hypermutation of A:T bases in Ig genes because humans deficient for the polymerase have fewer substitutions of these bases. To determine whether polymerase eta is also responsible for the well-known preference for mutations of A vs T on the nontranscribed strand, we sequenced variable regions from three patients with xeroderma pigmentosum variant (XP-V) disease, who lack polymerase eta. The frequency of mutations in the intronic region downstream of rearranged J(H)4 gene segments was similar between XP-V and control clones; however, there were fewer mutations of A:T bases and correspondingly more substitutions of C:G bases in the XP-V clones (p < 10(-7)). There was significantly less of a bias for mutations of A compared with T nucleotides in the XP-V clones compared with control clones, whereas the frequencies for mutations of C and G were identical in both groups. An analysis of mutations in the WA sequence motif suggests that polymerase eta generates more mutations of A than T on the nontranscribed strand. This in vivo data from polymerase eta-deficient B cells correlates well with the in vitro specificity of the enzyme. Because polymerase eta inserts more mutations opposite template T than template A, it would generate more substitutions of A on the newly synthesized strand.
OBJECTIVE: We compared hemodynamic values, oxygen utilization, and adenine nucleotide concentration in the extracted organs of brain-dead donors treated with triiodothyronine vs. standard support treatment. DESIGN: Prospective, randomized, double-blind controlled study. PATIENTS: We recruited 52 consecutive adult cadaveric organ donors. Inclusion criteria were diagnosis of brain-death, transplantation suitability, and family consent for donation; exclusion criterion was preexisting thyroid disease. INTERVENTIONS: The treatment group (n=29) received an intravenous bolus of 1 microg/kg triiodothyronine followed by continuous perfusion at 0.06 microg/kg per hour, and controls (n=23) received 0.9% ClNa delivered over 270 min. Hemodynamics, tonometry, thyroid hormones, and serum lactate were measured every 90 min from brain death to extraction procedure. Biopsies were processed to determine adenine nucleotides concentration. RESULTS: Hemodynamic measurements did not differ significantly in the two groups, and the inotrope dose could not be diminished after treatment. Thyrotropin levels increased from brain death to extraction procedure in controls. Thyrotropin measured 90 and 180 min after the beginning of the perfusion was significantly lower in the treatment group than controls. The Pco2 gap increased in both groups from brain death to the extraction procedure. The lactate level of the treatment group was lower than in controls. Biopsy specimens were obtained in 19 controls and in 20 donors of the treatment group; the adenine nucleotides concentration did not show any significant difference. CONCLUSIONS: Triiodothyronine did not add any benefit over the standard management of the organ donor nor did it affect the adenine nucleotides concentration of any biopsied organs.