Structural Insights into the Roles of Metazoan-Specific Splicing Factors in the Human Step 1 Spliceosome

Bertram, K.; Ayoubi, Leyla El; Dybkov, Olexandr; Agafonov, Dmitry E.; Will, Cindy L.; Hartmuth, Klaus; Urlaub, Henning; Kastner, Berthold; Stark, Holger; Lührmann, Reinhard

doi:10.1016/j.molcel.2020.09.012

Cited by 38 publications

(33 citation statements)

References 69 publications

(73 reference statements)

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“…Among the ArgRS binding partners, SRRM2 was highly and reproducibly enriched in both 293T and HepG2 cells (Figure 2A, B, upper right and lower left, Supplementary Table S5). We subsequently focused on SRRM2 because of its significance as a part of the spliceosome (Blencowe et al, 2000; Zhang et al, 2017; Bertram et al, 2020) and as an essential component for nuclear speckle formation (Hu et al, 2019; Ilik et al, 2020; Miyagawa et al, 2012). We confirmed the interaction between ArgRS and SRRM2 in both HepG2 and 293T cell lysates by reciprocal co-immunoprecipitation and western blotting (Supplementary Figure S1E, F), while MetRS, another component of the nuclear MSC, was not enriched by SRRM2 pulldown (Supplementary Figure S1G).…”

Section: Resultsmentioning

confidence: 99%

Arg-tRNA synthetase links inflammatory metabolism to RNA splicing and nuclear trafficking via SRRM2

Cui

Diedrich

et al. 2021

Preprint

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Cells respond to perturbations such as inflammation by sensing changes in metabolite levels. Especially prominent is arginine, which has long known connections to the inflammatory response. Here we show that depletion of arginine during inflammation decreased levels of arginyl-tRNA synthetase (ArgRS) in the nucleus. We found that nuclear ArgRS interacted with serine/arginine repetitive matrix protein 2 (SRRM2) in membrane-less, condensate-like, SRRM2-dependent nuclear speckles. This interaction impeded SRRM2 speckle trafficking and resulted in changes in alternative mRNA splicing. Splice site usage was regulated in opposite directions by ArgRS and SRRM2. These ArgRS- and SRRM2-dependent splicing changes cumulated in synthesis of different protein isoforms that altered cellular metabolism and peptide presentation to immune cells. Our findings delineate a novel mechanism whereby a tRNA synthetase responds to a metabolic change and modulates the splicing machinery via condensate trafficking for cellular responses to inflammatory injury.

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Section: Resultsmentioning

confidence: 99%

Arg-tRNA synthetase links inflammatory metabolism to RNA splicing and nuclear trafficking via SRRM2

Cui

Diedrich

et al. 2021

Preprint

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“…FRG1 protein is part of human spliceosomal complex C 25 . Earlier studies primarily focused on the role of FRG1 in FSHD.…”

Section: Discussionmentioning

confidence: 99%

Role of FRG1 in predicting the overall survivability in cancers using multivariate based optimal model

Khan

Palo

Dixit

2021

Sci Rep

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FRG1 has a role in tumorigenesis and angiogenesis. Our preliminary analysis showed that FRG1 mRNA expression is associated with overall survival (OS) in certain cancers, but the effect varies. In cervix and gastric cancers, we found a clear difference in the OS between the low and high FRG1 mRNA expression groups, but the difference was not prominent in breast, lung, and liver cancers. We hypothesized that FRG1 expression level could affect the functionality of the correlated genes or vice versa, which might mask the effect of a single gene on the OS analysis in cancer patients. We used the multivariate Cox regression, risk score, and Kaplan Meier analyses to determine OS in a multigene model. STRING, Cytoscape, HIPPIE, Gene Ontology, and DAVID (KEGG) were used to deduce FRG1 associated pathways. In breast, lung, and liver cancers, we found a distinct difference in the OS between the low and high FRG1 mRNA expression groups in the multigene model, suggesting an independent role of FRG1 in survival. Risk scores were calculated based upon regression coefficients in the multigene model. Low and high-risk score groups showed a significant difference in the FRG1 mRNA expression level and OS. HPF1, RPL34, and EXOSC9 were the most common genes present in FRG1 associated pathways across the cancer types. Validation of the effect of FRG1 mRNA expression level on these genes by qRT-PCR supports that FRG1 might be an upstream regulator of their expression. These genes may have multiple regulators, which also affect their expression, leading to the masking effect in the survival analysis. In conclusion, our study highlights the role of FRG1 in the survivability of cancer patients in tissue-specific manner and the use of multigene models in prognosis.

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“…FRG1 protein is part of human spliceosomal complex C [21]. Earlier studies primarily focused on the role of FRG1 in facioscapulohumeral muscular dystrophy (FSHD).…”

Section: Discussionmentioning

confidence: 99%

“…8) which shows four types of functions where FRG1 might be involved namely, pre-mRNA processing (CWC22), mitochondrial functioning (MRPS18C, MRPL1, MRPL54, and NDUFC1), ribosomal functioning (RPL34, RPL24), and in DNA damage/repair pathway (HPF1, PARP1, SUMO2). FRG1 with CWC22 interact [24] and they both are also part of the spliceosomal C complex [21]. Deregulation of these genes may have a direct effect on spliceosome complex functioning.…”

Section: Discussionmentioning

confidence: 99%

Role of FRG1 in predicting the overall survivability in cancers using multivariate based optimal model

Khan

Palo

Dixit

2021

Preprint

View full text Add to dashboard Cite

FRG1 has a role in tumorigenesis and angiogenesis. Our preliminary analysis showed FRG1 expression is associated with the overall survival (OS) in cancers the effect varies. In cervix and gastric cancers, we found a clear difference in the OS between the low and high FRG1 expression groups, but in breast, lung, and liver cancers the difference was not prominent. We hypothesized that the functionality of the genes correlated with FRG1 could be getting affected by FRG1 or vice versa, which might mask the effect of a single gene on the OS analysis in cancer patients. We used the multivariate Cox regression, risk score, and Kaplan Meier analyses to determine OS in a multigene model. STRING, Cytoscape, and HIPPIE were used to deduce FRG1 associated pathways. In breast, lung, and liver cancer we found a distinct difference in the OS, between the low and high FRG1 expression groups in the multigene model, suggesting an independent role of FRG1 in survival. Risk scores were calculated based upon regression coefficients in the multigene model. Low and high-risk score groups revealed a significant difference in the FRG1 expression and survival. HPF1, RPL34, and EXOSC9 were the most common genes present in FRG1 associated pathways across the cancer types. Validation of the effect of FRG1 expression on these genes by qRT-PCR, supports that FRG1 might be an upstream regulator of their expression. These genes may have multiple regulators which also affect their expression, leading to the masking effect in the survival analysis. In conclusion, our study highlights the role of FRG1 in the survivability of cancer patients in tissue-specific manner and the use of multigene models in prognosis.

show abstract

Structural Insights into the Roles of Metazoan-Specific Splicing Factors in the Human Step 1 Spliceosome

Cited by 38 publications

References 69 publications

Arg-tRNA synthetase links inflammatory metabolism to RNA splicing and nuclear trafficking via SRRM2

Arg-tRNA synthetase links inflammatory metabolism to RNA splicing and nuclear trafficking via SRRM2

Role of FRG1 in predicting the overall survivability in cancers using multivariate based optimal model

Role of FRG1 in predicting the overall survivability in cancers using multivariate based optimal model

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