Functional significance of U2AF1 S34F mutations in lung adenocarcinomas

Esfahani, Mohammad Shahrokh; Lee, Luke J.; Jeon, Young-Jun; Flynn, Ryan A.; Stehr, Henning; Hui, Angela Bik‐Yu; Ishisoko, Noriko; Kildebeck, Eric J.; Newman, Aaron M.; Bratman, Scott V.; Porteus, Matthew H.; Chang, Howard Y.; Alizadeh, Ash A.; Diehn, Maximilian

doi:10.1038/s41467-019-13392-y

Cited by 35 publications

(33 citation statements)

References 69 publications

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“…However, the S34F and S34Y mutants bind 5′-UCAGGU with K d values of 0.77 μM and 0.63 μM, respectively, similar values as that for 5′-UUAGGU (Table 1 ). These ITC results are consistent with the previous analysis of lung adenocarcinomas that S34F mutant prefers 3′SS sequences, including a CAG motif 20 , 21 . In contrast to wild-type U2AF1, therefore, the S34Y and S34F mutants show little discrimination for the base at −3 position, except for rejecting guanosine.…”

Section: Resultssupporting

confidence: 92%

“…However, whole-exome sequence analysis by Ilagan et al, Kim et al, and Okeyo-Owuor et al showed that A or C are found much more frequently at the −3 position of the 3′SS ((A/C)AG) recently, if Ser34 is replaced by Phe or Tyr in hematological malignancies 17 – 19 . In addition, Fei et al and Esfahani et al reported that in lung adenocarcinomas, the U2AF1 S34F mutant preferentially binds to CAG at 3′SS, unlike wild-type U2AF1 20 , 21 . These results suggested that while the wild-type protein requires −3U to function efficiently, these pathogenic mutants of U2AF1 can accept A or C at this position.…”

Section: Resultsmentioning

confidence: 99%

“…Using genome-wide analysis, Ilagan et al, Kim et al, and Okeyo-Owuor et al recently reported that the S34F/Y mutations of U2AF1 change the preferred 3′SS and enhance aberrant exon inclusion 17 – 19 , leading to hematological malignancies, including myelodysplastic syndromes (MDS). Furthermore, very recently, Fei et al and Esfahani et al elucidated by genomic analysis and iCLIP-RNA sequencing that the S34F mutant of U2AF1 causes aberrant alternative splicing in lung adenocarcinomas 20 , 21 . In spite of its importance, the molecular mechanism of sequence-specific RNA recognition by U2AF1 has been poorly understood, especially from a structural point of view.…”

Section: Introductionmentioning

confidence: 99%

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Elucidation of the aberrant 3′ splice site selection by cancer-associated mutations on the U2AF1

et al. 2020

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The accurate exclusion of introns by RNA splicing is critical for the production of mature mRNA. U2AF1 binds specifically to the 3´ splice site, which includes an essential AG dinucleotide. Even a single amino acid mutation of U2AF1 can cause serious disease such as certain cancers or myelodysplastic syndromes. Here, we describe the first crystal structures of wild-type and pathogenic mutant U2AF1 complexed with target RNA, revealing the mechanism of 3´ splice site selection, and how aberrant splicing results from clinically important mutations. Unexpected features of this mechanism may assist the future development of new treatments against diseases caused by splicing errors.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Elucidation of the aberrant 3′ splice site selection by cancer-associated mutations on the U2AF1

et al. 2020

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“…It may be speculated that MPN patients with PPM1D mutations may be more prone to development of second cancer. Importantly, several other MPN-associated mutations such as ASXL1 , SH2B3 , TET2 , JAK2 , TP53 , KRAS , NRAS , and U2AF1 are found in other cancers as well [ 92 , 202 , 203 , 204 , 205 ]. Indeed, studies have shown that patients with MPNs have a higher risk of developing second cancer [ 206 , 207 , 208 ].…”

Section: Ngs In the Diagnosis And Prognosis Of Mpnsmentioning

confidence: 99%

Next Generation Sequencing in MPNs. Lessons from the Past and Prospects for Use as Predictors of Prognosis and Treatment Responses

Skov

2020

Cancers

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The myeloproliferative neoplasms (MPNs) are acquired hematological stem cell neoplasms characterized by driver mutations in JAK2, CALR, or MPL. Additive mutations may appear in predominantly epigenetic regulator, RNA splicing and signaling pathway genes. These molecular mutations are a hallmark of diagnostic, prognostic, and therapeutic assessment in patients with MPNs. Over the past decade, next generation sequencing (NGS) has identified multiple somatic mutations in MPNs and has contributed substantially to our understanding of the disease pathogenesis highlighting the role of clonal evolution in disease progression. In addition, disease prognostication has expanded from encompassing only clinical decision making to include genomics in prognostic scoring systems. Taking into account the decreasing costs and increasing speed and availability of high throughput technologies, the integration of NGS into a diagnostic, prognostic and therapeutic pipeline is within reach. In this review, these aspects will be discussed highlighting their role regarding disease outcome and treatment modalities in patients with MPNs.

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“…Approximately 50% of MDS, 20% of acute myeloid leukemia (AML) and 60% of chronic myelomonocytic leukemia (CMML) harbor heterozygous somatic mutations in the spliceosome genes SF3B1, U2AF1, SRSF2, and ZRSR2, which are involved in the early stage of spliceosome assembly and cause distinct changes in RNA splicing and gene expression 9,10,11,12,13,14,15,16,17,18,19,20,21 . Many solid tumors, including uveal melanoma, breast, lung and pancreatic cancers, also harbor spliceosome gene mutations 22,23,24,25,26 .…”

Section: Introductionmentioning

confidence: 99%

Nonsense Mediated RNA Decay Is a Unique Vulnerability of Cancer Cells with SF3B1 and U2AF1 Mutations

Cheruiyot¹,

Li²,

Srivatsan³

et al. 2021

Preprint

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Nonsense-mediated RNA decay (NMD) is well recognized as an RNA surveillance pathway that targets aberrant mRNAs with premature translation termination codons (PTCs) for degradation; however, its molecular mechanisms and roles in health and disease remain incompletely understood. In this study, we developed a novel reporter system that can accurately measure NMD activity in individual cells. By carrying out a genome-wide CRISPR/Cas9 knockout screen using this reporter system, we identified novel NMD-promoting factors, including multiple components of the SF3B complex and other U2 spliceosome factors. Interestingly, we also found that cells with mutations in the U2 spliceosome genes SF3B1 and U2AF1—which are commonly found in myelodysplastic syndrome (MDS) and cancers—have overall attenuated NMD activity. Furthermore, we found that compared to wild type cells, SF3B1 and U2AF1 mutant cells are more sensitive to NMD inhibition, a phenotype that is accompanied by elevated DNA replication obstruction, DNA damage and chromosomal instability. Remarkably, the sensitivity of spliceosome mutant cells to NMD inhibition could be rescued by overexpression of RNase H1, which removes R-loops in the genome. Together, our findings shed new light on the functional interplay between NMD and RNA splicing and suggest a novel strategy for the treatment of MDS and cancers with spliceosome mutations.

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Functional significance of U2AF1 S34F mutations in lung adenocarcinomas

Cited by 35 publications

References 69 publications

Elucidation of the aberrant 3′ splice site selection by cancer-associated mutations on the U2AF1

Elucidation of the aberrant 3′ splice site selection by cancer-associated mutations on the U2AF1

Next Generation Sequencing in MPNs. Lessons from the Past and Prospects for Use as Predictors of Prognosis and Treatment Responses

Nonsense Mediated RNA Decay Is a Unique Vulnerability of Cancer Cells with SF3B1 and U2AF1 Mutations

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