PubMed · 6264706
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B S Naroditskiĭ, S N Khil'ko, V N Loparev. 1981. [Current methods of isolating specific endonucleases].. https://pubmed.ncbi.nlm.nih.gov/6264706/
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Homing endonuclease genes (HEGs) are selfish genetic elements that spread by first cleaving chromosomes that do not contain them and then getting copied across to the broken chromosome as a byproduct of the repair process. The success of this strategy will depend on the opportunities for homing--in other words, the frequency with which HEG(+) and HEG(-) chromosomes come into contact--which varies widely among host taxa. HEGs are also unusual in that the selection pressure for endonuclease function disappears if they become fixed in a population, which makes them susceptible to degeneration and imposes a need for regular horizontal transmission between species. HEGs will be selected to reduce the harm done to the host organism, and this is expected to influence the evolution of their sequence specificity and maturase functions. HEGs may also be domesticated by their hosts, and are currently being put to human uses.
The origin of the progressive spinocerebellar ataxic disorder 'Machado Joseph Disease (MJD)' has been attributed solely to an expansion mutation resulting from an autosomal dominant inheritance of an unstable CAG repeat in chromosome 14q32.1 of the MJD gene that encodes for the synthesis of ataxin 3. The faulty gene has purportedly been disseminated since the Middle Ages into Azorean, Dutch and Makassan communities by an international trading community based in NE-central Portugal. However, following improvements in MJD surveillance, the MJD afflicted families that have been identified in increasing numbers of familial clusters of MJD being discovered around the world--e.g. in Aboriginal, Yemenite, Asian and Japanese populations--cannot be connected back to the original Portuguese founder families, but rather implicates an environmental factor, superimposed on a genetic flaw. An analytical study of the isolated ecosystems supporting both the Portuguese and non-Portuguese MJD affected communities demonstrates a common abnormal hallmark of high manganese (Mn)/low magnesium (Mg) status, suggesting that this aberrant mineral ratio inactivates the Mn/Mg catalyzed endonuclease 1 enzyme in the biosystems of those who are dependent upon these ecosystems. Endonuclease activity is crucial for protecting against the expansion/contraction of the trinucleotide repeats in the genes that encode for proteins such as Ataxin 3--the 'mutant' chaperone protein that hallmarks the central nervous system (CNS) of MJD sufferers. It is proposed that MJD, and possibly the other more common expansion mutation diseases such as Friedrich's Ataxia and Huntingdon's Chorea, are multifactorial diseases caused by a hitherto unrecognised autosomal dominant inherited failure to regulate Mn/Mg metabolism in populations living in high Mn/low Mg ecosystems. Mg supplementation of the 'at risk' populations during the 'in utero' developmental stages could be all that is required to maintain healthy endonuclease turnover, thereby protecting MJD susceptible genotypes against this fatal, progressive neurodegenerative disease.
The current model for influenza virus mRNA transcription involves the sequential interaction of the viral polymerase with the 5'- and 3'-ends of vRNA, with each RNA-protein interaction triggering a polymerase function necessary for cap-primed transcription. Here we show that the order in which this ternary complex is assembled is in fact important. Polymerase bound simultaneously to a pre-annealed duplex of the 5'- and 3'-ends of vRNA had greatly increased levels of primer binding and endonuclease activities compared to a sequentially assembled complex. Increased primer binding was due to the activation of a high affinity binding site with a preference for primer length RNAs. This correlated with enhanced levels of cap-primed transcription. Polymerase that was bound initially to just 5' vRNA had low primer binding activity, but was endonucleolytically active. Neither activity was significantly increased by the subsequent addition of 3' vRNA, and this sequentially assembled complex had correspondingly low mRNA transcription activity. Nevertheless, both routes of assembly led to complexes that were highly competent for dinucleotide ApG-primed transcription. Therefore, polymerase complexes assembled on pre-annealed 5' and 3' terminal viral RNA sequences have distinct properties from those assembled by sequential loading of polymerase onto the 5'-end followed by the 3'-end. This suggests a mechanism by which the virus couples transcription initiation and termination during mRNA transcription.