The augmented R-loop is a unifying mechanism for myelodysplastic syndromes induced by high-risk splicing factor mutations Journal Article

Authors: Chen, L.; Chen, J. Y.; Huang, Y. J.; Gu, Y.; Qiu, J.; Qian, H.; Shao, C.; Zhang, X.; Hu, J.; Li, H.; He, S.; Zhou, Y.; Abdel-Wahab, O.; Zhang, D. E.; Fu, X. D.
Article Title: The 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 (MDSs) and solid tumors. These mutations have generally been assumed to cause disease by the resultant splicing defects, but different mutations appear to induce distinct splicing defects, raising the possibility that an alternative common mechanism is 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 ataxia telangiectasia and Rad3-related protein (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 loses its ability to extract the RNA polymerase II (Pol II) C-terminal domain (CTD) kinase—the positive transcription elongation factor complex (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 the MDS phenotype. Chen et al. report that myelodysplastic syndrome-associated mutations in splicing factors, including SRSF2 and U2AF1, cause cell growth defects through elevated R-loops, replication stress, and ATR-Chk1 activation. Mutant SRSF2 induces transcription pausing and, thus, R-loops, possibly because of its compromised ability in extracting p-TEFb from the 7SK complex at TSSs. © 2017 Elsevier Inc.
Keywords: signal transduction; controlled study; protein phosphorylation; promoter region; somatic mutation; comparative study; mutant protein; dna replication; cell proliferation; phenotype; gene overexpression; carboxy terminal sequence; myelodysplastic syndrome; alternative rna splicing; protein secretion; doxycycline; atr protein; rna polymerase ii; myeloid progenitor cell; short hairpin rna; rna binding; mds; ribonuclease h; r-loops; dna demethylation; g2 phase cell cycle checkpoint; human; article; genome instability; hek293t cell line; splicing factor mutations
Journal Title: Molecular Cell
Volume: 69
Issue: 3
ISSN: 1097-2765
Publisher: Cell Press  
Date Published: 2018-02-01
Start Page: 412
End Page: 425.e6
Language: English
DOI: 10.1016/j.molcel.2017.12.029
PROVIDER: scopus
PUBMED: 29395063
Notes: Article -- Export Date: 1 March 2018 -- Source: Scopus
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