TOP3B, short for topoisomerase III beta, is a member of the topoisomerase family. It operates on both DNA and RNA substrates, playing crucial roles in regulating gene expression and genomic stability [2]. It is involved in pathways related to R-loop resolution and is essential for maintaining genome integrity. Mutations in TOP3B are linked to neurodevelopmental and cognitive disorders, highlighting its significance for human health [2].

A homozygous deletion of the TOP3B gene in a patient with bilateral renal cancer led to genome instability, an increase in DNA damage, chromosome bridging, and a significant rise in R-loop formation, suggesting TOP3B is necessary to prevent excessive R-loop accumulation [1]. In TOP3B knockout cells, elevated R-loops were observed, which could be suppressed by TOP3B transfection. R-loop-inducing agents also induced higher R-loops in these knockout cells. TOP3B physically associates with R-loops and can cleave the single-stranded DNA displaced by the R-loop RNA-DNA duplex. It interacts with the R-loop helicase DDX5 to resolve R-loops in a pathway parallel with senataxin [3].

In conclusion, TOP3B is vital for resolving R-loops and maintaining genome stability. Its loss-of-function models, such as gene knockout in cells or in patients, have revealed its role in preventing genomic damage. These findings are significant for understanding diseases like cancer and neurodevelopmental disorders where TOP3B mutations or deletions are implicated [1,3].