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
Quinlan, A. R., & Hall, I. M. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq033 · Cited by 27,437
Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes
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“…mutations are not restricted to MDS; they have also been identified in various solid tumors, such as melanoma (Furney et al., 2013; Harbour et al., 2013; Martin et al., 2013) and bladder (Papaemmanuil et al., 2011), pancreatic (Biankin et al., 2012), and lung (Imielinski et al., 2012) cancer.”
Frequent pathway mutations of splicing machinery in myelodysplasia
Yoshida, K., Sanada, M., Shiraishi, Y., Nowak, D., Nagata, Y., Yamamoto, R., Sato, Y., Sato-Otsubo, A., Kon, A., Nagasaki, M., et al. (2011) · Nature · doi:10.1038/nature10496 · Cited by 2,029
ATR: an essential regulator of genome integrity
Cimprich, K. A., & Cortez, D. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2450 · Cited by 1,798
Mapping the Hallmarks of Lung Adenocarcinoma with Massively Parallel Sequencing
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Somatic mutation in cancer and normal cells
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Somatic SF3B1 Mutation in Myelodysplasia with Ring Sideroblasts
Papaemmanuil, E., Cazzola, M., Boultwood, J., Malcovati, L., Vyas, P., Bowen, D., Pellagatti, A., Wainscoat, J. S., Hellstrom-Lindberg, E., Gambacorti-Passerini, C., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1103283 · Cited by 1,222
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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Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo
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The core spliceosome as target and effector of non-canonical ATM signalling
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Myelodysplastic syndrome: An inability to appropriately respond to damaged DNA?
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“…various observations have pointed to the association of genome instability with MDS (Colla et al., 2015; Makishima et al., 2017; Nguyen et al., 2017; Zhou et al., 2013), our data unveil a potential mechanism for increased but limited genome instability because of augmented R-loop formation.”
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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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