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The nuclear pore: a safe place for gene expression

Via the formation of toxic hybrids between DNA and mRNA, the process of gene expression can lead to mutations and other genetic alterations. In an article published in Nature Communications, researchers from Institut Jacques-Monod and iRCM merged imaging and biochemistry approaches to show that the genes involved in expression are conducted to nuclear pores in order to protect the genome.

Published on 3 October 2023

The maintenance of genome stability requires tightly regulated coordination between the different activities involving DNA. Notably, high transcription levels can lead to the development of DNA/mRNA hybrids, called "R-loops." These latter can become toxic structures, disturbing replication and causing damage to DNA. How thus does the cellular machinery regulate gene activity without creating a risk for the integrity of the genetic material?

In a study published in Nature Communications, researchers from Institut Jacques-Monod and the Laboratory of Genome Instability and Nuclear Organization (LION - iRCM) sought to respond to just that question. To do so, the team studied the genetic location of R-loop formation using microscopic imaging and pangenomics techniques in the nuclei of living S. cerevisiae yeasts. They were thus able to show that single-strand DNA is initially detected by the trimeric replication protein A (RPA), an essential complex already known to play a role in DNA replication and repair. They furthermore showed that SUMOylation (the attachment of small ubiquitin-like modifiers ("SUMO") to a target protein) of RPA "tags" concerned genes, ensuring their interaction with the nuclear pore, which is known for its role in the exchange of molecules between the nucleus and the rest of the cell. 

It appears that once in that nuclear pore environment, the R-loops are eliminated, possibly facilitated by the export of involved mRNAs, and, in that manner, any associated genetic instability is prevented.

A balance between high gene expression and DNA stability maintenance

Similar mechanisms have already been observed in a range of situations where cellular DNA sustains damage or is exposed to therapies that alter genetic integrity. In this setting, the reorganization of damaged DNA enables its repair at the nuclear pore. When gene products are needed in great number, particularly in response to stress, these mechanisms reconcile high gene expression (i.e., high levels of mRNA synthesis) and DNA stability preservation, thus minimizing the risk of genetic damage or mutations caused by R-loops. ​

The results published by the Monod-iRCM team shed light on the detection mechanisms for these structures and lay a path toward a better understanding of their roles not only in genome biology but also in the human diseases they are associated with, most notably certain cancers and neurological syndromes.

Contact researcher : Karine Dubrana

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