Xrn2 is a 5'-to-3' exoribonuclease mainly located in the nucleus [1,5]. It is evolutionarily conserved in eukaryotes and plays essential roles in gene expression processes like transcription termination and ribosome biogenesis by degrading or trimming various RNAs [1,5]. It also contributes to DNA damage response, R-loop resolution, and is involved in multiple cellular pathways such as DNA repair/replication and RNA metabolism [3,4,6,7].

Loss-of-function experiments have revealed its significance. In glioblastomas, loss of XRN2 decreases cell motility, invasion, and abolishes tumor formation in orthotopic mouse xenografts [2]. In BRCA1-mutant cells, RNF8 deficiency reduces XRN2 occupancy at R-loop-prone sites, promoting R-loop accumulation and genomic instability, highlighting its role in R-loop resolution [3]. XRN2 depletion also compromises cell survival when specific DNA repair proteins like PARP1 are knocked down, showing a synthetic lethal relationship [4]. In addition, XRN2-deficient cells have increased R-loops, genomic instability, and replication stress, and a delay in DSB repair [7].

In conclusion, XRN2 is crucial for multiple biological processes including transcription, R-loop resolution, and DNA repair. Loss-of-function studies, especially in mouse models, have shown its importance in diseases such as glioblastomas and BRCA1-mutant-related cancers, providing insights into potential therapeutic targets.