Stress-Induced Nuclear Import Governs Transcription Recovery after DNA Damage

The DNA damage response (DDR) preserves genome integrity by transiently halting RNA polymerase II (RNAPII)-mediated transcription during lesion repair. Here, we identify stress-induced nuclear import as a key regulator of RNA synthesis recovery (RRS). Inhibition of IMPα/β1-dependent nuclear import sensitizes cells to UV irradiation by impairing RRS, without affecting DNA repair. We further show that a fraction of the RNA/DNA exonuclease EXD2 translocates from the mitochondria to the nucleus in response to UV-induced stress. In the nucleus, EXD2 interacts with RNAPII, promotes degradation of nascent mRNA, and facilitates transcription restart. Disruption of EXD2’s nuclear localization signal mimics import inhibition, abolishing its interaction with RNAPII, blocking RRS, and reducing cell survival after UV exposure. Remarkably, forced nuclear localization of EXD2 restores RRS and UV resistance, even when nuclear import is compromised. Strikingly, persistent nuclear localization of EXD2 in the absence of stress is detrimental, causing mitotic defects. Our findings establish stress-induced IMPα/β1-dependent nuclear import as a critical DDR checkpoint, identify EXD2 as its key effector, and underscore the importance of spatial and temporal control of nuclease activity in maintaining genome stability.