Researchers from the Bellvitge Biomedical Research Institute (IDIBELL), led by Julian Cerón, have demonstrated the dual function of a protein, RSR-2, both in the DNA transcription machinery as in the RNA maturation complex (splicing) in the worm C. elegans. It is the first time that this dual function of a protein in a living multicellular organism has been confirmed .
RSR-2 protein is conserved from yeast to humans. The results of the study are published in the journal PLoS Genetics.
Gene Transcription and splicing
DNA encoding proteins passes through several stages to synthesize them. In this process there are two machineries: the transcription complex in which DNA passes to RNA and the RNA processing complex (splicing) which involves the removal of sequence fragments called introns.
As IDIBELL researcher Julian Cerón explains, “it has been shown in cell lines and in vitro that proteins from the two machineries interact physically, and that proteins of the transcription machinery are present in the splicing machinery and vice-versa. However, the functional interaction in both machineries had not been studied before in a living multicellular organism”.
Researchers generated transgenic animals and an antibody against the protein RSR-2 in order to observe where was the protein and they saw that “as we expected, it was interacting with DNA sequences with introns and therefore involved in splicing, but also we observed that the protein was associated with genes without introns and therefore also involved in the process of gene transcription”, explains Cerón.
Interaction with retinoblastoma pathway
In previous research, Julian Cerón, had identified a genetic interaction between the RSR-2 gene with the retinoblastoma pathway a genetic pathway deregulated in most human tumors, “but as RSR-2 belonged to the splicing machinery and retinoblastoma participates in the remodelling of chromatin in the transcription machinery, we did not know how to interpret this interaction”.
Proving that RSR-2 also works in DNA transcription Ceron implies that “we have found the missing piece of the puzzle. If retinoblastoma and RSR-2 need each other to work, it opens the door to changing RSR-2 as a novel therapeutic strategy against cancer”.
Target for Retinitis Pigmentosa
RSR-2 protein could also be a new therapeutic target in human blindness for a specific type of retinitis pigmentosa. PRP8 mutations present in the splicing machinery cause a type of progressive blindness known as retinitis pigmentosa. Cerón team has shown that the RSR-2, like its counterparts in yeast and humans, interacts with the gene PRP8 opening the door to new therapies through the modification of RSR-2.
Article reference
Laura Fontrodona, Montserrat Porta-de-la-Riva, Tomás Morán, Wei Niu, Mònica Díaz, David Aristizábal-Corrales, Alberto Villanueva, Simó Schwartz Jr, Valerie Reinke, Julián Cerón (2013) RSR-2, the Caenorhabditis elegans Ortholog of Human Spliceosomal Component SRm300/SRRM2, Regulates Development by Influencing the Transcriptional Machinery. PLoS Genet 9(6): e1003543. doi:10.1371/journal.pgen.1003543.