A nuclear trafficking checkpoint licenses resolution of RNA–DNA hybrids at stalled RNAPII to maintain genome stability under genotoxic stress

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Abstract Genotoxic stress inhibits transcription, generating RNA–DNA hybrid intermediates that promote toxic transcription–replication conflicts (TRCs). Here, we show that genotoxic stress triggers transient Importin-α/β1-dependent nuclear import of the mitochondrial exonuclease EXD2 to resolve these conflicts and maintain genome stability. Mechanistically, once imported into the nucleus, EXD2 is recruited to elongation-arrested RNA polymerase II (RNAPII) associated with RNA–DNA hybrids, and its exonuclease activity limits their accumulation, thereby suppressing TRCs. Mutation of a putative EXD2 nuclear localization signal phenocopies disruption of nuclear import, whereas forced nuclear targeting of EXD2 bypasses it. However, sustained nuclear localization of EXD2 leads to mitotic defects, underscoring the importance of its tight spatial regulation. Consistent with a direct role for EXD2 in RNA–DNA hybrid resolution, overexpression of the ribonuclease RNaseH1 compensates for its depletion following DNA damage. Together, our findings introduce the concept of a trafficking-dependent checkpoint that transiently licenses EXD2 nuclease activity in the nucleus in response to genotoxic stress to resolve RNA–DNA hybrid intermediates at stalled RNAPII complexes Teaser Stress-triggered nuclear import of EXD2 resolves harmful RNA–DNA hybrids to protect genome stability after DNA damage.

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