The DOI matches its Crossref record; 13 of the 13 references it cites were found in a registry or an index.
The Augmented R-Loop Is a Unifying Mechanism for Myelodysplastic Syndromes Induced by High-Risk Splicing Factor Mutations
Open accessAbstract
SUMMARY 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.
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Cites
BEDTools: a flexible suite of utilities for comparing genomic features
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Frequent pathway mutations of splicing machinery in myelodysplasia
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ATR: an essential regulator of genome integrity
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Somatic SF3B1 Mutation in Myelodysplasia with Ring Sideroblasts
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Intragenic DNA methylation prevents spurious transcription initiation
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SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition
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Self-citationObeng, E. A., Chappell, R. J., Seiler, M., Chen, M. C., Campagna, D. R., Schmidt, P. J., Schneider, R. K., Lord, A. M., Wang, L., Gambe, R. G., et al. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.08.006 · Cited by 380
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Metadata
- 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.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 69
- Issue
- 3
- Pages
- 412-425.e6
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2786842416
- Cited by
- 299
- References
- 13
- FWCI
- 9.50
- Type
- journal article
- Language
- en
- Open access
- bronze
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- 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. (2018). The Augmented R-Loop Is a Unifying Mechanism for Myelodysplastic Syndromes Induced by High-Risk Splicing Factor Mutations. Molecular Cell. https://doi.org/10.1016/j.molcel.2017.12.029
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