If it holds up, the model, which is now guiding laboratory experiments for confirmation, could re-establish the reputation of proteins as the original self-replicating biomolecule.
For scientists studying the origin of life , one of the greatest chicken-or-the-egg questions is: Which came first — proteins or nucleic acids like DNA and RNA? Four billion years ago or so, basic chemical building blocks gave rise to longer polymers that had a capacity to self-replicate and to perform functions essential to life: namely, storing information and catalyzing chemical reactions. Which one could have originally handled both jobs on its own? For decades, the favored candidate has been RNA — particularly since the discovery in the s that RNA can also fold up and catalyze reactions, much as proteins do.
But RNA is also incredibly complex and sensitive , and some experts are skeptical that it could have arisen spontaneously under the harsh conditions of the prebiotic world. Moreover, both RNA molecules and proteins must take the form of long, folded chains to do their catalytic work, and the early environment would seemingly have prevented strings of either nucleic acids or amino acids from getting long enough.
Ken Dill, a biophysicist at Stony Brook University, has been studying protein folding for decades. As models go, theirs is very simple. His hydrophobic-polar HP protein-folding model treats the 20 amino acids as just two types of subunit, which he likened to different colored beads on a necklace: blue, water-loving beads polar monomers and red, water-hating ones nonpolar monomers.
The model can fold a chain of these beads in sequential order along the vertices of a two-dimensional lattice, much like placing them on contiguous squares of a checkerboard. Which square a given bead ends up occupying depends on the tendency for the red, hydrophobic beads to clump together so that they can better avoid water. Dill, a biophysicist, used this kind of computation throughout the s to answer questions about the energy landscapes and folding states of protein sequences.
It is likely that this activity could be improved through evolution, ultimately enabling the synthesis of complete DNA genomes. DNA is much more stable compared to RNA and thus provides a larger and more secure repository for genetic information. Short-chain fatty acids SCFAs acetate, propionate, and butyrate are produced in large quantities by the gut microbiome and contribute to a wide array of physiological processes.
Here, we systematically investigate how SCFAs alter the epigenome. Using quantitative proteomics of histone modification states, we identified rapid and sustained increases in histone acetylation after the addition of butyrate or propionate, but not acetate. While decades of prior observations would suggest that hyperacetylation induced by SCFAs are due to inhibition of histone deacetylases HDACs , we found that propionate and butyrate instead activate the acetyltransferase p Recently it was reported that UCH37 activity is stimulated by branched ubiquitin chain architectures.
To understand how UCH37 achieves its unique debranching specificity, we performed biochemical and NMR structural analyses and found that UCH37 is activated by contacts with the hydrophobic patches of both distal ubiquitins that emanate from a branched ubiquitin.
In addition, RPN13, which recruits UCH37 to the proteasome, further enhances branched-chain specificity by restricting linear ubiquitin chains from having access to the UCH37 active site. In cultured human cells under conditions of proteolytic stress, we show that substrate clearance by the proteasome is promoted by both binding and deubiquitination of branched polyubiquitin by UCH Proteasomes containing UCH37 C88A , which is catalytically inactive, aberrantly retain polyubiquitinated species as well as the RAD23B substrate shuttle factor, suggesting a defect in recycling of the proteasome.
These findings provide a foundation to understand how proteasome degradation of substrates modified by a unique ubiquitin chain architecture is aided by a DUB. However, the information needed to make proteins is stored in DNA molecules. So which came first, proteins or DNA? The discovery in the s that RNA could fold like a protein, albeit not into such complex structures, suggested an answer. And if that was the case, RNA replicators would have had no need for proteins. They could do everything themselves.
It was an appealing idea, but at the time it was complete speculation. No one had shown that RNA could catalyse reactions like protein enzymes. It was not until , after decades of searching, that an RNA enzyme was finally discovered. Thomas Cech of the University of Colorado in Boulder found it in Tetrahymena thermophila , a bizarre single-celled animal with seven sexes Science , vol , p After that the floodgates opened. People discovered ever more RNA enzymes in living organisms and created new ones in their labs.
RNA might be not be as good for storing information as DNA, being less stable, nor as versatile as proteins, but it was turning out to be a molecular jack of all trades. These RNA replicators may even have had sex. The RNA enzyme Cech discovered did not just catalyse any old reaction.
It was a short section of RNA that could cut itself out of a longer chain. This ability would greatly accelerate evolution, because innovations made by separate lineages of replicators could be brought together in one lineage.
For many biologists the clincher came in , when the structure of the protein-making factories in cells was worked out. Still, some issues remained. For one thing, it remained unclear whether RNA really was capable of replicating itself. If there ever was a self-replicator, it has long since disappeared. So biochemists set out to make one, taking random RNAs and evolving them for many generations to see what they came up with. It is nucleotides long, but the longest RNA it can make contains just It reliably copies RNA sequences up to 95 letters long, almost half as long as itself Science , vol , p To do this, tC19Z clamps onto the end of an RNA, attaches the correct nucleotide, then moves forward a step and adds another.
These results raised two questions: 1 Why does RNA play so many roles in the flow of genetic information? RNA has great capability as a genetic molecule; it once had to carry on hereditary processes on its own. It now seems certain that RNA was the first molecule of heredity, so it evolved all the essential methods for storing and expressing genetic information before DNA came onto the scene. However, single-stranded RNA is rather unstable and is easily damaged by enzymes. By essentially doubling the existing RNA molecule, and using deoxyribose sugar instead of ribose, DNA evolved as a much more stable form to pass genetic information with accuracy.
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