In Silico Analysis of a Highly Mutated Gene in Cancer Provides Insight into Abnormal mRNA Splicing: Splicing Factor 3B Subunit 1K700E Mutant

Samy, Asmaa; Süzek, Barış E.; Özdemir, Mehmet Kemal; Şensoy, Özge

doi:10.3390/biom10050680

Cited by 6 publications

(6 citation statements)

References 73 publications

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“…2. Among the mutated codons, 700 account for more than 50% of the variants observed, and additional codons (666, 662, 622, and 625) have been found to be hotspots for mutation [41,[53][54][55].…”

Section: Sf3b1 Mutations In Cancermentioning

confidence: 99%

The biological function and clinical significance of SF3B1 mutations in cancer

et al. 2020

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Spliceosome mutations have become the most interesting mutations detected in human cancer in recent years. The spliceosome, a large, dynamic multimegadalton small nuclear ribonucleoprotein composed of small nuclear RNAs associated with proteins, is responsible for removing introns from precursor mRNA (premRNA) and generating mature, spliced mRNAs. SF3B1 is the largest subunit of the spliceosome factor 3b (SF3B) complex, which is a core component of spliceosomes. Recurrent somatic mutations in SF3B1 have been detected in human cancers, including hematological malignancies and solid tumors, and indicated to be related to patient prognosis. This review summarizes the research progress of SF3B1 mutations in cancer, including SF3B1 mutations in the HEAT domain, the multiple roles and aberrant splicing events of SF3B1 mutations in the pathogenesis of tumors, and changes in mutated cancer cells regarding sensitivity to SF3B small-molecule inhibitors. In addition, the potential of SF3B1 or its mutations to serve as biomarkers or therapeutic targets in cancer is discussed. The accumulated knowledge about SF3B1 mutations in cancer provides critical insight into the integral role the SF3B1 protein plays in mRNA splicing and suggests new targets for anticancer therapy.

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Section: Sf3b1 Mutations In Cancermentioning

confidence: 99%

The biological function and clinical significance of SF3B1 mutations in cancer

et al. 2020

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“…21 However, the molecular basis of mutation-induced aberrant 3′ splice site selection remains elusive. 6,18,22,23 To decrypt the molecular mechanisms underpinning aberrant 3′splice site selection in the presence of the K700E mutation, we established the impact of K700E mutation on pre-mRNA recognition by coupling all-atom molecular dynamics (MD) simulations with dynamical network theory analysis (NWA). 25,26 To this aim, we performed 1 μs long MD simulations on two SF3b models containing the wild type or K700E SF3B1 protein (hereafter named as WT and MUT, Figures 1A and S2).…”

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confidence: 99%

Cancer-Related Mutations Alter RNA-Driven Functional Cross-Talk Underlying Premature-Messenger RNA Recognition by Splicing Factor SF3b

Spinello

Janoš

Rozza

et al. 2023

J. Phys. Chem. Lett.

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The pillar of faithful premature-messenger (pre-mRNA) splicing is the precise recognition of key intronic sequences by specific splicing factors. The heptameric splicing factor 3b (SF3b) recognizes the branch point sequence (BPS), a key part of the 3′ splice site. SF3b contains SF3B1, a protein holding recurrent cancer-associated mutations. Among these, K700E, the most-frequent SF3B1 mutation, triggers aberrant splicing, being primarily implicated in hematologic malignancies. Yet, K700E and the BPS recognition site are 60 Å apart, suggesting the existence of an allosteric cross-talk between the two distal spots. Here, we couple molecular dynamics simulations and dynamical network theory analysis to unlock the molecular terms underpinning the impact of SF3b splicing factor mutations on pre-mRNA selection. We establish that by weakening and remodeling interactions of pre-mRNA with SF3b, K700E scrambles RNA-mediated allosteric cross-talk between the BPS and the mutation site. We propose that the altered allostery contributes to cancer-associated missplicing by mutated SF3B1. This finding broadens our comprehension of the elaborate mechanisms underlying pre-mRNA metabolism in eukaryotes.

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“…Recent mapping of cancer-associated mutations in SF3B1 suggested that these mutations disturb HEAT repeat domains, thus affecting the binding of SF3B1 with SF3B complex protein p14 and U2AF2 [ 298 , 299 ]. SF3B1 was also affected by the specific hotspot mutations that are associated with specific tumors.…”

Section: Defects In Splicing and Cancermentioning

confidence: 99%

Regulation of Pre-mRNA Splicing: Indispensable Role of Post-Translational Modifications of Splicing Factors

Kretova

Selicky

Cipakova

et al. 2023

Life

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Pre-mRNA splicing is a process used by eukaryotic cells to generate messenger RNAs that can be translated into proteins. During splicing, the non-coding regions of the RNAs (introns) are removed from pre-mRNAs and the coding regions (exons) are joined together, resulting in mature mRNAs. The particular steps of splicing are executed by the multimegadalton complex called a spliceosome. This complex is composed of small nuclear ribonucleoproteins, various splicing factors, and other regulatory and auxiliary proteins. In recent years, various post-translational modifications of splicing factors have been shown to contribute significantly to regulation of processes involved in pre-mRNA splicing. In this review, we provide an overview of the most important post-translational modifications of splicing factors that are indispensable for their normal function during pre-mRNA splicing (i.e., phosphorylation, acetylation, methylation, ubiquitination and sumoylation). Moreover, we also discuss how the defects in regulation of splicing factors are related to the development of cancer.

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In Silico Analysis of a Highly Mutated Gene in Cancer Provides Insight into Abnormal mRNA Splicing: Splicing Factor 3B Subunit 1K700E Mutant

Cited by 6 publications

References 73 publications

The biological function and clinical significance of SF3B1 mutations in cancer

The biological function and clinical significance of SF3B1 mutations in cancer

Cancer-Related Mutations Alter RNA-Driven Functional Cross-Talk Underlying Premature-Messenger RNA Recognition by Splicing Factor SF3b

Regulation of Pre-mRNA Splicing: Indispensable Role of Post-Translational Modifications of Splicing Factors

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