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Danny Incarnato, assistant professor of molecular genetics at the University of Groningen, and his colleague Robert C.
Spitale published an invited review of dynamic RNA structure and its function in Nature review
Genetics.
Image source: University of Groningen
The human genome has just over 20,000 genes
encoding proteins.
However, it produces at least ten times as many non-coding RNA molecules that can often take on more than one shape
.
At least some RNA structures are functional
in physiology or pathophysiology.
In an invited commentary, Nature Review Genetics Molecular geneticist Danny Incarnato and his colleague Robert C.
Spitale from the University of California, Irvine, a professor at the University of California, describe how to exploit the untapped potential
of RNA structures.
Their paper was published Nov
.
8.
RNA is best known as an intermediate between the genome and protein synthesis: messenger RNA molecules replicate the genetic code of genes in the nucleus and transport it to the cytoplasm, where ribosomes translate the code into proteins
.
However, RNA is also a key regulator of almost every cellular process, and the structure adopted by RNA molecules is often considered key
to their function.
Danny Incarnato, assistant professor of molecular genetics, has long been interested in the role of RNA structures in cells and has worked on ways
to elucidate different structures in living cells.
So, when he was asked to write a review of RNA structure, he didn't hesitate to accept
.
"I am delighted to have my friend and colleague Robert Spitale, one of
the pioneers of the 'RNA revolution'.
"
In recent years, the understanding of RNA molecules within cells has grown
significantly.
The ENCODE project revealed a large number of non-coding RNAs in cells; In human cells, there are more than
ten times the number of genes that code.
Incarnato emphasizes: "Not all products have features
.
" "But a lot of it is, and we're only scratching the surface of their species
.
"
Different types of noncoding RNAs have long been known, and it is clear that their structure plays an important role
in this.
The riboswitch is an example: the RNA can change shape in response to changes in the external environment, which in turn affects specific gene activity
.
"We also know that RNA molecules can act as enzymes," Incarnato said
.
"Of course, ribosomes are RNA structures
.
" Thus, RNA molecules can act as sensors, catalysts, switches, or scaffolds, influencing RNA translation, but can also affect RNA degradation and selective splicing
.
”
Therefore, it is not surprising that RNA is gaining momentum quickly in drug research
.
However, our understanding of "structure" is still very limited
.
"So far, we've studied almost only individual structures
.
But RNA molecules are very dynamic, and molecules with the same sequence can take on different shapes," Incarnato explains
.
"Because of the way these structures are determined, they are usually averages
of all possible conformations of a single molecule.
"
Incarnato pioneered methods
to reveal the structural heterogeneity of RNA molecules.
"We can combine high-throughput RNA sequencing to probe for structural heterogeneity
.
In some cases, the different structures are just 'by-products of evolution', while in others they are functional
.
"Incarnato:"In this way, RNA molecules regulate almost anything inside the cell and, therefore, play a role
in both physiology and pathophysiology.
Although this area is developing very rapidly, they are not carried out
in a very orderly manner.
Incarnato said: "In parallel with a lot of basic research, there is also applied pharmaceutical research
.
Interfering with RNA can be an important way to fight diseases, including those caused by RNA viruses, such as SARS-CoV2
.
However, we do not yet have a clue
about off-target effects.
For small molecules that interfere with specific enzymes, such as kinases, analytical plates can be used to evaluate off-target profiles
.
However, we don't know how many RNAs have similar shapes
.
We really need a clear picture
of the RNA structure.
”
Another problem is that in many cases it is impossible to know which different structural version of a particular RNA molecule is responsible for its function or dysfunction
.
"Beyond that, RNA can interact and create complex regulatory networks
.
Therefore, we also need to understand more deeply how this works
in cells.
”
There is still a lot of work to be done
.
In addition, software is important; Computer programs are needed to translate the biochemical analysis of RNA into different structures
.
Incarnato: "In our field, you need to understand coding as much as high-throughput sequencing
.
All of us are in the lab and in bioinformatics
.
”
Probing the dynamic RNA structurome and its functions