Functionally interdependent editing and methylation

By: James V. Kohl | Published on: April 4, 2017

Editing and methylation at a single site by functionally interdependent activities

…cytosine 32 in the anticodon loop of Trypanosoma brucei tRNAThr is methylated to 3-methylcytosine (m3C) as a pre-requisite for C-to-U deamination. Formation of m3C in vitro requires the presence of both the T. brucei m3C methyltransferase TRM140 and the deaminase ADAT2/3. Once formed, m3C is deaminated to 3-methyluridine (m3U) by the same set of enzymes. ADAT2/3 is a highly mutagenic enzyme4, but we also show that when co-expressed with the methyltransferase its mutagenicity is kept in check.

They showed how natural selection for energy-dependent codon optimality is linked from autophagy to RNA-directed DNA methylation and supercoiled DNA, which protects all organized genomes from virus-driven energy theft.
Reported as: Electric DNA, Circular RNA, and Other Epigenetic Wonders

…some non-coding RNAs are now known to be ‘guardian RNAs’ according to the modifications on their bases or sugars with methyl groups that act as tags.

The energy-dependent de novo creation of nucleic acids links microRNAs in flanking sequences to hydrogen-atom transfer in DNA base pairs in solution. Virus-driven energy theft causes the failure of hydrogen-atom transfer in DNA base pairs in solution, which links mutations to all pathology.
For additional claims about all pathology see: The Most Transformational Biologist of Our Era?
Dr Zhang: I worked with John to figure out how the HIV virus put different components together. We used the retrovirus as a model, and that formed the basis for the project.
Dr Zhang: …I realized that psychiatric disease is very much a physical illness, just like cancer or diabetes.
Dr Zhang: Optogenetics allows us to use light to stimulate specific groups of cells to be able to systematically map out how the brain is wired and how things work.
Dr Zhang: I did not know what CRISPR was. I went to look it up. Around that time, a paper from Sylvain Moineau in Canada was published describing how it was RNA-guided endonuclease.
Dr Zhang: Editas Medicine is a gene-editing company that I cofounded with George Church, Jennifer Doudna, Keith Joung, and David Liu. The mission of Editas is to develop the CRISPR genome-editing system for clinical applications. More than 5000 genetic diseases are caused by specific mutations in our cells. We thought it would be great if we could build a platform that systematically developed this to treat the many diseases for which we know the cause but have no way of treating.
Dr Topol:

We applaud you for what you have done to transform this field, along with so many others around the world. You really have been a pioneer. We look forward to seeing your work translated into something that will be therapeutic for people; especially the people who are often neglected—those with rare, Mendelian diseases. Congratulations on what you have already achieved. Just think what is in store.

For an example of what is for sale in Harvard’s store, see:
RNA-Guided Human Genome Engineering

…use of gRNAs [guide RNAs] provide the ability to multiplex than mRNAs in part due to the smaller size—100 vs. 2000 nucleotide lengths respectively. This is particularly valuable when nucleic acid delivery is size limited, as in viral packaging. This enables multiple instances of cleavage, nicking, activation, or repression—or combinations thereof. The ability to easily target multiple regulatory targets allows the coarse-or-fine-tuning or regulatory networks without being constrained to the natural regulatory circuits downstream of specific regulatory factors (e.g. the 4 mRNAs used in reprogramming fibroblasts into IPSCs).

5. Repetitive elements or endogenous viral elements can be targeted with engineered Cas+gRNA systems in microbes, plants, animals, or human cells to reduce deleterious transposition or to aid in sequencing or other analytic genomic/transcriptomic/proteomic/diagnostic tools (in which nearly identical copies can be problematic).

FIG. 3A-1 and FIG. 3A-2 depict a human codon-optimized version of the Cas9 protein and full sequence of the cas9 gene insert.

Natural selection for energy-dependent codon-optimality links feedback loops from food odors and pheromones to the physiology of reproduction in all living genera.
Codon identity regulates mRNA stability and translation efficiency during the maternal-to-zygotic transition

The bias between codons or amino acids, and mRNA expression levels has been previously recognized across species and is thought to result from selection for efficient, accurate translation, and folding of highly expressed genes (Ikemura,
1982; Akashi, 1994; Akashi & Gojobori, 2002; Drummond & Wilke, 2008; Kudla et al, 2009; Novoa & Ribas de Pouplana, 2012). The amino acid optimality code (Fig 6) provides an alternative perspective on sequence changes between paralogs in evolution and human disease.

Get Well in the RNAi Way-RNAi, A Billion Dollar Baby in Therapy

Disease therapy based on genetic materials is now a reality. The technique of gene silencing also called as RNA interference (RNAi) keeps our hopes alive. RNAi based drugs have now advanced steps closer towards clinical trials. The powerful in-vivo RNAi machinery and its delicate factors apprehend that RNAi-dependent therapies might create a billion dollar business against the pathogenic organisms and disease for which treatment options are currently restricted conventionally. Recent years have highlighted both the promises and challenges in delivery of different RNAi therapeutics. Apart from the delivery, the design, stability and degradation of RNAi based effective molecules appears to be the major lime light to challenge the conventional drug safety concerns and ensures to be the most powerful gene recovery in future which execute billion dollar business hope.

The billion dollar business hype exemplifies the failure of all pseudoscientists to recognize the fact that energy-dependent changes in microRNAs link hydrogen-atom transfer in DNA base pairs in solution to all biodiversity via the physiology of reproduction in species from microbes to humans.
See for comparison: Pheromones and the luteinizing hormone for inducing proliferation of neural stem cells and neurogenesis
Feedback loops link odor and pheromone signaling with reproduction (2005)
Dynamic control of chirality and self-assembly of double-stranded helicates with light
Dependence of RNA synthesis in isolated thymus nuclei on glycolysis, oxidative carbohydrate catabolism and a type of “oxidative phosphorylation” (1964)

The synthesis of RNA in isolated thymus nuclei is ATP dependent.

A protein conjugation system essential for autophagy (1998)

This conjugation can be reconstituted in vitro and depends on ATP. To our knowledge, this is the first report of a protein unrelated to ubiquitin that uses a ubiquitination-like conjugation system. Furthermore, Apg5 and Apg12 have mammalian homologues, suggesting that this new modification system is conserved from yeast to mammalian cells.

The Intrinsically Disordered Protein Atg13 Mediates Supramolecular Assembly of Autophagy Initiation Complexes 

One hallmark of autophagy is sequestration of a portion of cytoplasm by de novo formation of a double-membrane structure, the autophagosome, which fuses with lytic compartments (vacuoles in yeast and plants; lysosomes in mammals), leading to degradation of its contents.

The senior author is the 2016 Nobel Laureate, Yoshinori Ohsumi. He placed these findings into the context of the de novo formation of a double-membrane structure and supramolecular assembly of intrinsically disordered proteins. The authors make no mention of the facts about how the energy-dependent biosynthesis of RNA must be linked to supercoiled DNA, which protects all organized genomes from virus-driven energy theft in the context of autophagy and the physiology of reproduction.

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