A new step towards understanding the splicing mechanism, "snip and stitch ", by which cells convert genetic information into a form suitable for protein synthesis. The study published in ACS Catalysis by Istituto Officina dei Materiali (Iom) of the National Research Council (Cnr) in collaboration with the National Institute of Chemistry, Ljubljana, Slovenia, explains for the first time how the second phase of the chemical mechanism of splicing occurs. This knowledge is needed to find possible treatments for diseases related to incorrect splicing, such as leukaemias and other types of cancer
A study by the Istituto Officina dei Materiali (IOM) of the National Research Council (CNR) recently published in ACS Catalysis explains how the chemical mechanism of messenger RNA splicing takes place. The study focuses on a critical step in the formation of a mature messenger RNA. RNA is the nucleic acid, which together with the most famous DNA, constitutes the pillar of the genetic code. In eukaryotic cells, a complex molecular machinery called spliceosome performs a sophisticated “snipping and stitching” process that converts premature messenger RNA into a mature form ready to be used for protein synthesis.
For the synthesis of proteins, the cells use the information contained in messenger RNA, which is generated from some DNA sequences, called genes. However, in the genes, the DNA traits that code for proteins, called exons, are interspersed with long non-coding DNA sequences named introns. For this reason, the splicing process, in which cells accurately remove introns from a primary RNA strand and sew the exons together, is needed. A tiny mistake in this process leads to the formation of a wrong messenger RNA sequence, ultimately leading to defective proteins.
"The spliceosome is one of the most complex molecular machines of eukaryotic cells and is made by hundreds of proteins and five strands of RNA, which altogether form a dense network of interactions" as Alessandra Magistrato of Cnr-Iom explains. “The spliceosome acts in the same way in all eukaryotic cells, operating with an extremely complex and sophisticated mechanism that sometimes does not wok properly. When a mutation occurs (i.e. a change in one or more amino acids in the proteic part of this machinery) aberrant splicing can take place, triggering various pathological states among which leukemia, retinitis pigmentosa, melanoma, and breast cancer”, as Jure Borisek says.
The extreme complexity of this system has only recently allowed researches to move the first steps towards its detailed understanding at the atomic scale. However, this knowledge is mandatory to devise modulation strategies for treating, and sometimes for preventing the more than 200 diseases associated to mis-splicing events.
"Our study is carried out with sophisticated computer simulations, made only possible by modern supercomputers, which allow us to see at the atomic-level resolution how this meticoulous “snip and stitch” process takes place" adds Magistrato.
Who: Istituto Officina dei Materiali of National Council of Research (Cnr-Iom)
Che cosa: A study on the second phase of the splicing mechanism by which cells perform protein synthesis, DOI: 10.1021/acscatal.0c00390
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