Composite image of yeast nuclei whose genetic information (blue) features structures (orange) formed of RNA molecules that have inserted themselves into the DNA helix. Image credit: Sarah Isler and Shamayita Roy (CC BY 4.0)
Cells are constantly exposed to external and internal processes that threaten the integrity of their genetic information. Even small errors or physical defects in the DNA strands that store the instructions required for life can have wide-ranging consequences. In response, cells deploy a variety of molecular actors to repair these lesions before they cause issues.
R-loops are a particularly complex form of genetic damage that emerge when a molecule known as RNA inserts itself into the DNA helix. If left unaddressed, the resulting structure interferes with the machinery that allows cells to replicate or express their genes – potentially leading to serious harm for the organism. Indeed, R-loops are often present in genes linked to a variety of cancers and neurological disorders. Despite their importance, how R-loops are normally removed is still not fully understood.
To explore this question, Roy et al. focused on the Smc5/6 complex, a molecular machine found across the tree of life that can help repair structurally complex genetic lesions. The team tested its involvement in R-loop removal using yeast strains that tend to carry more of these defects.
Yeast cells genetically manipulated to lack functional Smc5/6 complexes accumulated toxic levels of R-loops, resulting in extreme growth defects. Further investigations showed that the complex particularly targeted R-loops forming in highly expressed genes, as well as in genetic sequences important for preserving DNA integrity. Finally, Roy et al. used biochemical assays to explore how the human Smc5/6 complex specifically recognizes R-loops and assists an enzyme called RNase H – which can degrade RNA – in removing them.
Taken together, these findings deepen our understanding of R-loop dynamics; going forward, they may also help explain why mutations in components of the Smc5/6 complex are associated with severe genetic disorders in humans.
