SRSF1 Prevents DNA Damage and Promotes Tumorigenesis through Regulation of DBF4B Pre-mRNA Splicing

Chen, Linlin; Luo, Chunling; Shen, Lei; Liu, Yuguo; Wang, Qianqian; Zhang, Chang; Guo, Ruochen; Zhang, Yanan; Xie, Zhiqin; Wei, Ning; Wu, Wenwu; Han, Jun; Feng, Ying

doi:10.1016/j.celrep.2017.11.091

Cited by 65 publications

(51 citation statements)

References 23 publications

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“…The maintenance of genomic stability is of paramount importance to living organisms including cancer cells; thus, many proteins including splicing factors and RNA surveillance factors have been known to participate in DNA damage response . Our studies have identified that CHERP/SR140 and UPF3A are novel players involved in DNA damage response, as loss of them leads to DSB and triggers spontaneous DNA damage response and cell death.…”

Section: Discussionmentioning

confidence: 79%

“…Levels of splicing factors such as SRSF1, SRSF6, SRSF10, hnRNPK or hnRNPLL are significantly altered in many types of cancer including CRC . Therefore, it is not surprising that dysregulated AS events can contribute to almost all hallmarks of cancer, including sustained proliferation and evasion of apoptosis .…”

Section: Discussionmentioning

confidence: 99%

“…RT‐PCR and qPCR were performed as previously described . In vivo crosslinking and immunoprecipitation (CLIP) of mRNA bound to CHERP or SR140 proteins was performed as previously described .…”

Section: Methodsmentioning

confidence: 99%

“…Mice xenografts were formalin‐fixed and paraffin‐embedded as previously described . For Ki‐67 staining, sections were incubated with Ki‐67 antibody as previously described . To determine the apoptotic cells in tumors, sections were performed with the TUNEL kit (Promega Corporation, Madison, WI).…”

Section: Methodsmentioning

confidence: 99%

“…RT-PCR and qPCR were performed as previously described. [17][18][19][20] In vivo crosslinking and immunoprecipitation (CLIP) of mRNA bound to CHERP or SR140 proteins was performed as previously described. 15,16 In brief, after transient transfection of HAtagged CHERP, SR140 plasmids or empty vector controls in 293T cells, ultraviolet cross-linking and sonication of cells were performed followed by immunoprecipitation using Magna RIP kit (Millipore, Burlington, MA).…”

Section: Rt-pcr Qpcr In Vivo Crosslinking and Immunoprecipitationmentioning

confidence: 99%

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U2‐related proteins CHERP and SR140 contribute to colorectal tumorigenesis via alternative splicing regulation

Wang

Liu

et al. 2019

Intl Journal of Cancer

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Dysregulation of calcium homeostasis endoplasmic reticulum protein (CHERP) has been implicated in several cancers, but it remains elusive how CHERP contributes to cancer cell proliferation and cancer development. Here, we observed that CHERP and its binding partner SR140 are significantly upregulated in human clinical colorectal cancer tissues (CRC). CHERP and SR140 could form a protein complex to stabilize each other. Knockdown of CHERP or SR140 triggers double‐stranded DNA breaks and cell death. Furthermore, UPF3A, the RNA surveillance factor, was identified as a splicing target of CHERP and SR140, which bind specifically to the regulated exon4 and modulate UPF3A splicing. UPF3A knockdown recapitulates CHERP/SR140 depletion both in vitro and in mice. Importantly, overexpression of UPF3A significantly rescues proliferation defect of CHERP/SR140‐depleted cells. These results confirmed that the effect of CHERP/SR140 in promoting tumorigenesis was partially mediated by UPF3A. Extending these results, upregulation of CHERP/SR140 observed in CRC remarkably parallels increased inclusion of UPF3A exon4. Together, our study clarifies how CHERP/SR140 exert an oncogenic role in CRC development partially through regulating expression of UPF3A variants.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Rt-pcr Qpcr In Vivo Crosslinking and Immunoprecipitationmentioning

confidence: 99%

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U2‐related proteins CHERP and SR140 contribute to colorectal tumorigenesis via alternative splicing regulation

Wang

Liu

et al. 2019

Intl Journal of Cancer

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RBFOX2/GOLIM4 Splicing Axis Activates Vesicular Transport Pathway to Promote Nasopharyngeal Carcinogenesis

Luo

Liu

et al. 2021

Advanced Science

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20–30% of patients with nasopharyngeal carcinoma (NPC) develop distant metastasis or recurrence leading to poor survival, of which the underlying key molecular events have yet to be addressed. Here alternative splicing events in 85 NPC samples are profiled using transcriptome analysis and it is revealed that the long isoform of GOLIM4 (‐L) with exon‐7 is highly expressed in NPC and associated with poor prognosis. Lines of evidence demonstrate the pro‐tumorigenic function of GOLIM4‐L in NPC cells. It is further revealed that RBFOX2 binds to a GGAA motif in exon‐7 and promotes its inclusion forming GOLIM4‐L. RBFOX2 knockdown suppresses the tumorigenesis of NPC cells, phenocopying GOLIM4‐L knockdown, which is significantly rescued by GOLIM4‐L overexpression. High expression of RBFOX2 is correlated with the exon‐7 inclusion of GOLIM4 in NPC biopsies and associated with worse prognosis. It is observed that RBFOX2 and GOLIM4 can influence vesicle‐mediated transport through maintaining the organization of Golgi apparatus. Finally, it is revealed that RAB26 interacts with GOLIM4 and mediates its tumorigenic potentials in NPC cells. Taken together, the findings provide insights into how alternative splicing contributes to NPC development, by highlighting a functional link between GOLIM4‐L and its splicing regulator RBFOX2 activating vesicle‐mediated transport involving RAB26.

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Single‐Cell RNA Sequencing Reveals Heterogeneity of Myf5‐Derived Cells and Altered Myogenic Fate in the Absence of SRSF2

et al. 2022

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Splicing factor SRSF2 acts as a critical regulator for cell survival, however, it remains unknown whether SRSF2 is involved in myoblast proliferation and myogenesis. Here, knockdown of SRSF2 in myoblasts causes high rates of apoptosis and defective differentiation. Combined conditional knockout and lineage tracing approaches show that Myf5-cre mice lacking SRSF2 die immediately at birth and exhibit a complete absence of mature myofibers. Mutant Myf5-derived cells (tdtomato-positive cells) are randomly scattered in the myogenic and non-myogenic regions, indicating loss of the community effect required for skeletal muscle differentiation. Single-cell RNA-sequencing reveals high heterogeneity of myf5-derived cells and non-myogenic cells are significantly increased at the expense of skeletal muscle cells in the absence of SRSF2, reflecting altered cell fate. SRSF2 is demonstrated to regulate the entry of Myf5 cells into the myogenic program and ensures their survival by preventing precocious differentiation and apoptosis. In summary, SRSF2 functions as an essential regulator for Myf5-derived cells to respond correctly to positional cues and to adopt their myogenic fate.

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SRSF1 Prevents DNA Damage and Promotes Tumorigenesis through Regulation of DBF4B Pre-mRNA Splicing

Cited by 65 publications

References 23 publications

U2‐related proteins CHERP and SR140 contribute to colorectal tumorigenesis via alternative splicing regulation

U2‐related proteins CHERP and SR140 contribute to colorectal tumorigenesis via alternative splicing regulation

RBFOX2/GOLIM4 Splicing Axis Activates Vesicular Transport Pathway to Promote Nasopharyngeal Carcinogenesis

Single‐Cell RNA Sequencing Reveals Heterogeneity of Myf5‐Derived Cells and Altered Myogenic Fate in the Absence of SRSF2

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