The sequence A–A–U–A–A–A is present in six different purified messenger RNA molecules (specifically the α- and β-globulin mRNAs of rabbit and human, the immunoglobulin light chain mRN A of mouse (MOPC 21) and the ovalbumin mRN A of chicken) about 20 residues away from the 3′-terminal poly(A) sequence. In addition, a large selection of the 3′ non-coding regions of rabbit and human globin mRN As (both the α- and β- globin mRN As) are 85% homologous, demonstrating that this region is significantly conserved in evolution.

3′ Non-coding region sequences in eukaryotic messenger RNA

Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus.

It is generally accepted that mutations may become fixed in a population by natural selection and genetic drift. In the case of many families of genes and noncoding sequences, however, fixation of mutations within a population may proceed as a consequence of molecular mechanisms of turnover within the genome. These mechanisms can be both random and directional in activity. There are circumstances in which the unusual concerted pattern of fixation permits the establishment of biological novelty and species discontinuities in a manner not predicted by the classical genetics of natural selection and genetic drift.

Molecular drive: a cohesive mode of species evolution

The recent discovery of reversible mRNA methylation has opened a new realm of post-transcriptional gene regulation in eukaryotes. The identification and functional characterization of proteins that specifically recognize RNA N6-methyladenosine (m6A) unveiled it as a modification that cells utilize to accelerate mRNA metabolism and translation. N6-adenosine methylation directs mRNAs to distinct fates by grouping them for differential processing, translation and decay in processes such as cell differentiation, embryonic development and stress responses. Other mRNA modifications, including N1-methyladenosine (m1A), 5-methylcytosine (m5C) and pseudouridine, together with m6A form the epitranscriptome and collectively code a new layer of information that controls protein synthesis.

/pdf/post-transcriptional-gene-regulation-by-mrna-modifications-5984s6cty9.pdf

Post-transcriptional gene regulation by mRNA modifications

Cachectin (tumor necrosis factor) is a macrophage hormone strongly implicated in the pathogenesis of endotoxin-induced shock. The availability of a DNA probe complementary to the cachectin messenger RNA (mRNA), as well as a specific antibody capable of recognizing the cachectin gene product, has made it possible to analyze the regulation of cachectin gene expression under a variety of conditions. Thioglycollate-elicited peritoneal macrophages obtained from mice contain a pool of cachectin mRNA that is not expressed as protein. When the cells are stimulated with endotoxin, large quantity of additional cachectin mRNA is produced, and immunoreactive cachectin is secreted. Macrophages from mice of the C3H/HeJ strain do not produce cachectin in response to endotoxin. A dual defect appears to prevent cachectin expression. First, a diminished quantity of cachectin mRNA is expressed in response to low concentrations of endotoxin. Second, a post-transcriptional defect prevents the production of cachectin protein. Macrophages from endotoxin-sensitive mice do not produce cachectin if they are first treated with dexamethasone, apparently for similar reasons. These findings give new insight into the nature of the C3H/HeJ mutation and suggest an important mechanism by which glucocorticoids may act to suppress inflammation.

https://science.sciencemag.org/content/sci/232/4753/977.full.pdf

Control of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance

DNA base sequence comparisons demonstrate that the principal family of 300-nucleotide interspersed human DNA sequences, the repetitive double-strand regions of HeLa cell heterogeneous nuclear RNA, and specific RNA polymerase III in vitro transcripts of cloned human DNA sequences are all representatives of a closely related family of sequences. A segment of approximately 30 residues of these sequences is highly conserved in mammalian evolution because it is also present in the interspersed repeated DNA sequences of Chinese hamsters. Further DNA sequence comparisons demonstrate that a portion of this highly conserved segment of repetitive mamalian DNA sequence is similar to a sequence found within a low molecular weight RNA that hydrogen-bonds to poly(A)-terminated RNA molecules of Chinese hamsters and a sequence that forms half of a perfect inverted repeat near the origin of DNA replication in papovaviruses.

https://www.pnas.org/content/pnas/77/3/1398.full.pdf

Ubiquitous, interspersed repeated sequences in mammalian genomes

Poly(A)-containing HeLa cell mRNA prepared from cells labeled with [methyl-(3)H]methionine or [(32)P]phosphate was found to contain a variety of methylated, blocked 5'-terminal structures of two general types: m(7)GpppN(7)-Np and m(7)GpppN(m)-N(m)-Np. In addition, about one-third of the [(3)H]methyl label was present in the N(6)-methyladenosine; this labeled nucleoside was not found in the 3'-terminal one-third of the mRNA chain and thus may also be in the 5' portion of the mRNA.

https://www.pnas.org/content/pnas/72/5/1904.full.pdf

Methylated, blocked 5 termini in HeLa cell mRNA.

https://www.cell.com/cell/pdf/0092-8674(77)90093-9.pdf

Warren Jelinek

Papers

Ubiquitous, interspersed repeated sequences in mammalian genomes

Methylated, blocked 5 termini in HeLa cell mRNA.

The definition of a large viral transcription unit late in Ad2 infection of HeLa cells: Mapping of nascent RNA molecular labeled in isolated nuclei

Methyl labeling of HeLa cell hnRNA: a comparison with mRNA.

Low molecular weight RNAs hydrogen-bonded to nuclear and cytoplasmic poly(a)-terminated RNA from cultured chinese hamster ovary cells