Spliceosome Mutations Induce R Loop-Associated Sensitivity to ATR Inhibition in Myelodysplastic Syndromes.

ABSTRACT: Heterozygous somatic mutations in spliceosome genes (U2AF1, SF3B1, ZRSR2, or SRSF2) occur in >50% of patients with myelodysplastic syndrome (MDS). 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 overexpressi

SUBMITTER: Nguyen HD 

PROVIDER: S-EPMC6139047 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature