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Augmented R-loop is a Unifying Mechanism for Myelodysplastic Syndromes Induced by High Risk Splicing Factor Mutations

ABSTRACT: Mutations in several general pre-mRNA splicing factors have been linked to Myelodysplastic Syndromes (MDS) and solid tumors. These mutations have generally been assumed to cause disease by resultant splicing defects, but different mutations appear to induce distinct splicing defects, raising a possibility for an alternative common mechanism involved. Here, we report a chain of events triggered by multiple splicing factor mutations, especially high-risk alleles in SRSF2 and U2AF1, including elevated R-loops, replication stress, and activation of the ATR-Chk1 pathway. We further demonstrate that enhanced R-loops, opposite to the expectation from gained RNA binding with mutant SRSF2, result from impaired transcription pause-release because the mutant protein lost its ability to extract the RNAPII CTD kinase P-TEFb from the 7SK complex. Enhanced R-loops are linked to compromised proliferation of bone marrow-derived blood progenitors, which can be partially rescued by RNase H overexpression, suggesting a direct contribution of augmented R-loops to MDS phenotype.

ORGANISM(S): Homo sapiens

PROVIDER: GSE97183 | GEO | 2018/01/04

SECONDARY ACCESSION(S): PRJNA380920

REPOSITORIES: GEO

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