Pan-cancer analysis identifies mutations in
            <i>SUGP1</i>
            that recapitulate mutant SF3B1 splicing dysregulation

Liu, Zhaoqi; Zhang, Jian; Sun, Yiwei; Perea-Chamblee, Tomin E.; Manley, James L.; Rabadán, Raúl

doi:10.1073/pnas.1922622117

Cited by 34 publications

(43 citation statements)

References 27 publications

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“…Our work not only confirms the results of Zhang et al [22] and Liu et al [32], but also extends them by demonstrating no detectable difference between SF3B1 mut and SUGP1 alt splice aberration patterns in cancers and in cellular models. We strengthen that only mutations with LOH are associated with 3′ss aberrant phenotype.…”

Section: Resultssupporting

confidence: 92%

Genetic alterations of SUGP1 mimic mutant-SF3B1 splice pattern in lung adenocarcinoma and other cancers

et al. 2020

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Genes involved in 3′-splice site recognition during mRNA splicing constitute an emerging class of oncogenes. SF3B1 is the most frequently mutated splicing factor in cancer, and SF3B1 mutants corrupt branchpoint recognition leading to usage of cryptic 3′-splice sites and subsequent aberrant junctions. For a comprehensive determination of alterations leading to this splicing pattern, we performed a pan-TCGA screening for SF3B1-specific aberrant acceptor usage. While the most of aberrant 3′-splice patterns were explained by SF3B1 mutations, we also detected nine SF3B1 wild-type tumors (including five lung adenocarcinomas). Genomic profile analysis of these tumors identified somatic mutations combined with loss-of-heterozygosity in the splicing factor SUGP1 in five of these cases. Modeling of SUGP1 loss and mutations in cell lines showed that both alterations induced mutant-SF3B1-like aberrant splicing. Our study provides definitive evidence that genetic alterations of SUGP1 genocopy SF3B1 mutations in lung adenocarcinoma and other cancers.

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Section: Resultssupporting

confidence: 92%

Genetic alterations of SUGP1 mimic mutant-SF3B1 splice pattern in lung adenocarcinoma and other cancers

et al. 2020

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“…SUGP1 (SURP And G-patch domain-containing protein, a member of the SURP family of splicing factors that likely interact with SF1 and RNA helicases) is also greatly reduced in samples from MDS patient harboring SF3B1 mutation [ 53 , 105 – 107 ]. Furthermore, loss or weakening of the interaction of SUGP1 with SF3B1 in the spliceosome was found to be the sole cause of defects in BP recognition, which results in the use of cryptic 3′ ss typically located 10–30 nt upstream of canonical 3′ ss [ 53 ].…”

Section: Functional Consequences Of Sf3b1 Mutationmentioning

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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“…Indeed, what other changes to the spliceosome cause DYNLL1 alternative-splicing is unknown. Recent work shows that loss of the splicing factor SUGP1 largely mimics the effects of SF3B1 hotspot mutations, suggesting an alternate mechanism that could affect DYNLL1 (47,48). Whether other Previous work has found that cancer-associated mutations of SF3B1 and other splicing factors cause R-loop accumulation and associated genome instability (29,31).…”

Section: Perspectivementioning

confidence: 99%

DYNLL1 mis-splicing is associated with replicative genome instability in SF3B1 mutant cells

Tsai

et al. 2021

Preprint

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Genome instability is a hallmark of cancer that arises through a panoply of mechanisms driven by oncogene and tumour-suppressor gene mutations. Oncogenic mutations in the core splicing factor SF3B1 have been linked to genome instability. Since SF3B1 mutations alter the selection of thousands of 3' splice sites affecting genes across biological pathways, it is not entirely clear how they might drive genome instability. Here we confirm that while R-loop formation and associated replication stress may account for some of the SF3B1-mutant genome instability, a mechanism involving changes in gene expression also contributes. An SF3B1-H662Q mutant cell line mis-splices the 5'UTR of the DNA repair regulator DYNLL1, leading to higher DYNLL1 protein levels, mis-regulation of DNA repair pathway choice and PARP inhibitor sensitivity. Reduction of DYNLL1 protein in these cells restores genome stability. Together these data highlight how SF3B1 mutations can alter cancer hallmarks through subtle changes to the transcriptome.

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Pan-cancer analysis identifies mutations in SUGP1 that recapitulate mutant SF3B1 splicing dysregulation

Cited by 34 publications

References 27 publications

Genetic alterations of SUGP1 mimic mutant-SF3B1 splice pattern in lung adenocarcinoma and other cancers

Genetic alterations of SUGP1 mimic mutant-SF3B1 splice pattern in lung adenocarcinoma and other cancers

The biological function and clinical significance of SF3B1 mutations in cancer

DYNLL1 mis-splicing is associated with replicative genome instability in SF3B1 mutant cells

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