Ribosome stalling as gene regulation?

Another cool paper from Mankin lab showed up in Nature Chemical Biology. This time researchers were looking at the detailed mechanism of translational arrest by two macrolide antibiotics, erythromycin and telithromycin.

Via series of mutations authors identified a single amino acid in the nascent peptide chain that determines selectivity and promiscuity of ribosome stalling by either of two antibiotics. To prove their point, they created an unnatural mutant gene with engineered selectivity to TEL.

While major implications of the study are dealing with antibiotic resistance and ways to overcome it, the authors coin an interesting evolutionary speculation. They suggest that the ribosome stalling could be another mechanism for gene regulation. In this case the sequence of some peptides could evolve in order to recognize small molecules during translation of the protein itself. And this could be another way to react on the environmental stimuli.

I guess that calls for another whole-transcriptome and cross-species genomic mining study for identification of such sequence−cofactor pairs.

By the way, a rare case, they did molecular dynamics simulation but didn’t include any pretty picture from it in the main text of the manuscript! That’s what happening when one has enough experimental data.

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Epi-epigenetics: RNA methylation (updated)

Two papers appeared online on February 10^th, to claim the first whole-transcriptome study of specific RNA modification, N¹-methylation of adenine (m¹A). To both teams’ credits, they cited each other as they learned about “competing” study.  Both papers, Li, Xiong et al. in Nature Chemical Biology and Dominissini, Nachtergaele, Moshitch-Moshkovitz et al. in Nature, overlap quite significantly but also complete each other in several aspects, and give starting insights into the role of RNA methylation in gene regulation.

Short life of biological dogmas

When you read a molecular biology textbook, it’s hard not to be amazed by the elegance and precision of cellular machinery. Everything is so logical, sequential, and organized to work properly. DNA templates self-copy and encodes RNA, which encodes proteins that do all kinds of work in a cell and organism. Francis Crick, who postulated this sequence, coined a term ‘the central dogma’ for it. And ever since ‘dogma’ became a buzzword for any fundamental assumption in molecular biology. But as with many assumptions in physics in the beginning of XX century, now many of these biological ‘dogmas’ are becoming obsolete. A recent review in Nuclear Acids Research discusses the premises for another dogma to fall.

Epigenetic ant reprogramming

Epigenetics is an exciting but a weird area. It’s well recognized that messing with chromatin and chemical modifications of nucleic acids has profound consequences at the cellular and organism levels. But for me the mechanistic rationale for targeting epigenome pharmacologically was always somewhere close to throwing a monkey wrench into the clockworks and watching what will happen. It seems (not surprisingly) that in fact the effects are more predictable.

Writing code for synthetic life

In the high school my chemistry teacher used to tell us that chemists do not only study the nature, but they also invent their own subject of study. The more I learn about biology, the more I feel that biologists move in the same direction, creating the new field of synthetic biology.

Recent report on the expansion of DNA alphabet by two letters grossly overshadowed not that press-release-friendly development in the synthetic biology of RNA. But there are quite some interesting things going on in the latter field that deserve as much attention.

ASOs for spinal muscular atrophy

In the new paper scientists from Isis Pharmaceuticals report on the development of the new mouse model for spinal muscular atrophy types I and II. The disease emerges from corrupted splicing of the SMN genes. The problem with previous models was that they were either too severe (with complete knockout of the ‘good’ protein), or too mild. So authors attempted to balance the copy number of the protein and create an ‘intermediate’ mouse line. They achieved that by combining ‘mild’ and ‘severe’ alleles and inserting additional human SMN2 gene into corresponding murine locus. So the resulting mice could live long enough and develop the expected neuromuscular pathology with relatively late onset of sympoms.

What’s more exciting is that when mutant mice were treated with the antisense oligo (ASO) targeting the pre-mRNA of SMN2 gene, the lethality and symptoms were improved. Even more surprising was the finding that delivery of the drug into CNS was not required for the improvement. The question remains if this feature translates into patients. Potentially this can lead to better understanding of the SMA pathology, namely if the disease originates in muscles or in neurons and what are the feedback loops between two cell types.