Discovery of a novel RNA class
Mitotic progression (cell division, from left to right) proceeds normally when nds-2a levels are intact (first row), however abnormal cell division is observed when nds-2a levels have been altered (middle and bottom row).
© Maximiliano Portal
(Cell divisions can be observed at video)
Nat Struct Mol Biol Jan 2015
Dec. 15, 2014
It has been known for nearly 60 years that RNA has the same potential as DNA to hybridize into a double helix.
However, in human cells the presence of stable double-stranded RNAs exerting biological roles that are critically dependent on this structure had never been experimentally demonstrated.
A study coordinated by Maximiliano Portal and Hinrich Gronemeyer at the IGBMC reports the existence of an entirely new class of stable non-coding double-stranded RNAs (termed 'ndsRNAs' for natural double-strand RNAs) which are naturally present in the nucleus of cells and regulate key cellular processes, such as cell division.
These results were published on December 15th in the journal Nature Structural and Molecular Biology.
Stable double-stranded RNAs are part of the human RNA repertoire
In eukaryotes, RNAs can be classified into two major groups according to whether they carry the information encoded by the DNA for protein synthesis (mRNA) or they rather play catalytic, regulatory or structural roles (non-coding RNAs). By developing a new RNA capture technique followed by strand-specific high-throughput sequencing, the team showed that a plethora of non-coding RNAs are potentially encoded by a genomic region containing markers associated with multiple diseases, yet considered as "silent". To their surprise, the team found that more than 20% of these new RNA molecules overlapped with a complementary RNA encoded on the opposite DNA strand, which suggested the existence of non-coding double stranded RNA. Notably, additional studies allowed the team to confirm that pairs of complementary RNA molecules generate stable non-coding double-stranded RNA mainly located in the cell nuclei, which they called "ndsRNA" for natural double-stranded RNAs.
ndsRNAs play key roles in cell physiology
To determine the biological relevance of ndsRNAs in human cells, the team focused on the characterization one of the members named “nds-2a”. They observed that the modification of nds-2a levels results in drastic changes in mitotic progression leading to abnormal cell division and / or cell death; results supporting that these novel molecules share the potential of regulating central aspects of cell physiology.
The presence of ndsRNA signatures throughout the genome, their interactions with protein complexes and the fact that the levels of certain ndsRNAs are modulated in response to treatments such as retinoic acid (a compound used in the treatment of leukemia patients) justifies a closer look to explore ndsRNA function and evaluate their utility as biomarkers and/or future therapeutic targets.
[The discovery of ndsRNAs has resulted in the filing of two patents. In addition, Maximiliano Portal received in 2014 a technology pre-maturation support for innovative projects from LabEx/SATT Conectus Alsace for the development of a novel technology allowing the high-throughput identification of ndsRNA molecules.]