Xrn2 is a 5'-to-3' exoribonuclease predominantly located in the nucleus. By degrading or trimming various RNA classes, it contributes to essential gene expression processes like transcription termination and ribosome biogenesis. It also plays roles in DNA repair, replication stress resolution, and telomere stability [1,3,5,6,7,8].

Loss of Xrn2 in glioblastoma cell lines decreases cellular speed, displacement, and invasion, and abolishes tumor formation in orthotopic mouse xenografts, indicating its importance in glioblastoma invasion [2]. Xrn2 -deficient fibroblast and lung cancer cells show sensitivity to PARP1 inhibition, uncovering a synthetic lethal relationship [3]. In Brca1 -mutant breast cancer cells, RNF8 deficiency decreases XRN2 occupancy at R-loop-prone sites, promoting R-loop accumulation and cancer cell death [4]. Xrn2-deficient cells have increased R-loops, genomic instability, replication stress, and DSBs, and exhibit a delay in DSB repair after ionizing radiation [7]. Depletion of XRN2 in ALT-positive cancer cells leads to increased TERRA R-loops and exacerbated ALT activity [8].

In conclusion, Xrn2 is crucial for multiple biological processes including transcription, DNA repair, and telomere stability. Studies using gene knockout models in cancer cell lines and mouse xenografts have revealed its significance in glioblastoma invasion, synthetic lethality with PARP1 inhibition, and telomere metabolism in ALT-positive cancer cells, providing potential therapeutic targets for these diseases.