Gene expression can lead to mutations or other forms of genetic changes through the formation of toxic hybrids between mRNA and DNA. In a paper published in the journal Nature Communications, scientists combined imaging and biochemical approaches to show that the genes that form these structures were housed and driven into nuclear pores to protect the integrity of the genome. Illustration image Pixabay
Maintaining genome stability requires highly regulated coordination of various activities that target DNA. In particular, high transcription rates can lead to the appearance of DNA/mRNA hybrids or “R-loops”, toxic structures that disrupt replication and lead to the appearance of damage in the DNA. How do cellular machines regulate gene activity without compromising the integrity of the genetic material? This is the question that scientists tried to answer in this study.
Using genome-wide approaches and live cell microscopy, scientists examined the localization of genes that form “R-loop” structures in the cell nucleus of the yeast S. cerevisiae. They were thus able to show that the single strand of DNA in these structures was first recognized by the trimeric protein RPA (replication protein A), an essential factor previously involved in DNA replication and repair.
They were also able to determine that coupling this protein to the small SUMO (Small Ubiquitin-like Modifier) ​​polypeptide then allowed “tagging” of the genes in question, thus ensuring their interaction with components of the nuclear pore known for their role in the exchange of molecules between the cell nucleus and the rest of the cell. In this setting, elimination of “R-loops,” a process possibly facilitated by export of the involved mRNAs via pores, would prevent the associated genetic instability.
A balance between high gene expression and maintaining DNA stability
For scientists, similar mechanisms have already been observed in various situations in which the cell’s DNA is exposed to damage or treatments that alter its genetic integrity. In this context, the reorganization of damaged DNA allows its repair at the level of nuclear pores. Therefore, when genes are expressed very actively, especially in response to stress, these mechanisms would allow high gene expression (i.e. high mRNA synthesis rates) and maintenance of DNA stability to be balanced, thus reducing the risk of mutations or genetic damage by minimizing stress “R-loops”.
These results thus shed new light on the recognition mechanisms of these structures and pave the way to understanding their role in the biology of the genome, but also in the various human pathologies to which they are associated, in particular cancers or neurological syndromes.
A, A model for the recognition and relocation of “R-loops” in the cell nucleus.
B: Microscopic evidence of a gene that forms “R-loops” (in orange) positioned at the level of nuclear pores (in blue) in live yeast.
© B. Palancade – IJM/CNRS
reference
An R-loop sensing pathway mediates the relocation of transcribed genes into nuclear pore complexes.
Penzo A, Dubarry M, Brocas C, Zheng M, Mangione RM, Rougemaille M, Goncalves C, Lautier O, Libri D, Simon MN, Geli V, Dubrana K, Palancade B.
Nature communication. 14(1):5606. Published online: September 20, 2023.