Spliceosome Mutations Induce R loop-Associated Sensitivity to ATR Inhibition in Myelodysplastic Syndrome

Heterozygous somatic mutations in spliceosome genes (U2AF1, SF3B1, ZRSR2, or SRSF2) occur in >50% of myelodysplastic syndrome (MDS) patients. These mutations occur early in disease development, suggesting that they contribute to MDS pathogenesis and may represent a unique genetic vulnerability for targeted therapy. Here we show that RNA splicing perturbation by expression of the U2AF1(S34F) mutant causes accumulation of R loops, a transcription intermediate containing RNA:DNA hybrids and displaced single-stranded DNA, and elicits an ATR response. ATR inhibitors (ATRi) induced DNA damage and cell death in U2AF1(S34F)-expressing cells, and these effects of ATRi were enhanced by splicing modulating compounds. Moreover, ATRi-induced DNA damage was suppressed by overexpression of RNaseH1, an enzyme that specifically removes the RNA in RNA:DNA hybrids, suggesting that the ATRi sensitivity of U2AF1(S34F)-expressing cells arises from R loops. Taken together, our results demonstrate that ATR may represent a novel therapeutic target in MDS patients carrying the U2AF1(S34F) mutation and potentially other malignancies harboring spliceosome mutations.

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