Rare SF3B1 R625 mutations in cutaneous melanoma

Kong, Yong; Krauthammer, Michael; Halaban, Ruth

doi:10.1097/cmr.0000000000000071

Cited by 50 publications

(43 citation statements)

References 9 publications

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“…2q33) have been reported in 1.8% of breast tumors, and more specifically in 4% of a subset of luminal breast tumors (Ellis et al 2012;Maguire et al 2015), and are significantly associated with the presence of estrogen-receptor (ER)-positive tumor cells, AKT1 mutations, and distinct copy-number alterations, including frequent chromosomal-segment gains on 16q12-q13 and 16q21-q22, and losses on 1p36-p35, 16q11-q13, and 16q21-q23 (Ellis et al 2012;Maguire et al 2015). SF3B1 mutations are also found at low frequency in pancreatic tumors (Biankin et al 2012), as well as melanoma (Furney et al 2013;Harbour et al 2013;Martin et al 2013;Kong et al 2014 ( Imielinski et al 2012). Interestingly, other splicing-factor mutations recurrent in blood malignancies, i.e., in SRSF2 or ZRSR2, have not yet been detected in solid tumors.…”

Section: Alterations In Splicing-factor Levels In Solid Tumorsmentioning

confidence: 99%

“…2). In addition, SF3B1 mutations of residues K700 and K666 have been reported in 1.8% of unselected breast tumors and 4% of luminal breast tumors (Ellis et al 2012;Maguire et al 2015), as well as in 3% of pancreatic ductal adenocarcinomas (Biankin et al 2012), whereas mutations of residues R625 and K666 are found in 15%-29% of uveal melanomas (Furney et al 2013;Harbour et al 2013;Martin et al 2013) and 1% of cutaneous melanomas (Table 1; Kong et al 2014).…”

Section: Recurrent Somatic Mutations Of Core Spliceosome Components Imentioning

confidence: 99%

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Splicing-factor alterations in cancers

Anczuków

Krainer

2016

RNA

235

247

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Tumor-associated alterations in RNA splicing result either from mutations in splicing-regulatory elements or changes in components of the splicing machinery. This review summarizes our current understanding of the role of splicing-factor alterations in human cancers. We describe splicing-factor alterations detected in human tumors and the resulting changes in splicing, highlighting cell-type-specific similarities and differences. We review the mechanisms of splicing-factor regulation in normal and cancer cells. Finally, we summarize recent efforts to develop novel cancer therapies, based on targeting either the oncogenic splicing events or their upstream splicing regulators.

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Section: Alterations In Splicing-factor Levels In Solid Tumorsmentioning

confidence: 99%

Section: Recurrent Somatic Mutations Of Core Spliceosome Components Imentioning

confidence: 99%

Splicing-factor alterations in cancers

Anczuków

Krainer

2016

RNA

235

247

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show abstract

“…Recurring hot spot mutations are found in myelodysplastic syndromes (Yoshida et al 2011), chronic lymphocytic leukemia (Landau et al 2013), chronic myelomonocytic leukemia (Patnaik et al 2013), uveal melanoma (Furney et al 2013), skin melanoma (Kong et al 2014), and breast (Ellis et al 2012) and pancreatic cancers (Biankin et al 2012). Spliceosome mutations are mutually exclusive and heterozygous and lead to missplicing of pre-mRNA to form aberrant transcripts.…”

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confidence: 99%

The cryo-EM structure of the SF3b spliceosome complex bound to a splicing modulator reveals a pre-mRNA substrate competitive mechanism of action

et al. 2018

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Somatic mutations in spliceosome proteins lead to dysregulated RNA splicing and are observed in a variety of cancers. These genetic aberrations may offer a potential intervention point for targeted therapeutics. SF3B1, part of the U2 small nuclear RNP (snRNP), is targeted by splicing modulators, including E7107, the first to enter clinical trials, and, more recently, H3B-8800. Modulating splicing represents a first-in-class opportunity in drug discovery, and elucidating the structural basis for the mode of action opens up new possibilities for structure-based drug design. Here, we present the cryogenic electron microscopy (cryo-EM) structure of the SF3b subcomplex (SF3B1, SF3B3, PHF5A, and SF3B5) bound to E7107 at 3.95 Å. This structure shows that E7107 binds in the branch point adenosine-binding pocket, forming close contacts with key residues that confer resistance upon mutation: SF3B1 R1074H and PHF5A Y36C . The structure suggests a model in which splicing modulators interfere with branch point adenosine recognition and supports a substrate competitive mechanism of action (MOA). Using several related chemical probes, we validate the pose of the compound and support their substrate competitive MOA by comparing their activity against both strong and weak pre-mRNA substrates. Finally, we present functional data and structure-activity relationship (SAR) on the PHF5A R38C mutation that sensitizes cells to some chemical probes but not others. Developing small molecule splicing modulators represents a promising therapeutic approach for a variety of diseases, and this work provides a significant step in enabling structure-based drug design for these elaborate natural products. Importantly, this work also demonstrates that the utilization of cryo-EM in drug discovery is coming of age.

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“…Importantly, these genes encode proteins that are all involved in 3 0 -splice site recognition during RNA splicing 4 . It has been shown that SF3B1 is mutated in a significant proportion (B20%) of uveal melanoma (UM), a rare malignant entity deriving from melanocytes from the uveal tract [5][6][7] , and in other solid tumours at lesser frequencies 8,9 .…”

mentioning

confidence: 99%

Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage

Alsafadi¹,

Houy²,

Battistella³

et al. 2016

European Journal of Cancer

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Hotspot mutations in the spliceosome gene SF3B1 are reported in B20% of uveal melanomas. SF3B1 is involved in 3 0 -splice site (3 0 ss) recognition during RNA splicing; however, the molecular mechanisms of its mutation have remained unclear. Here we show, using RNA-Seq analyses of uveal melanoma, that the SF3B1 R625/K666 mutation results in deregulated splicing at a subset of junctions, mostly by the use of alternative 3 0 ss. Modelling the differential junctions in SF3B1 WT and SF3B1 R625/K666 cell lines demonstrates that the deregulated splice pattern strictly depends on SF3B1 status and on the 3'ss-sequence context. SF3B1 WT knockdown or overexpression do not reproduce the SF3B1 R625/K666 splice pattern, qualifying SF3B1 R625/K666 as change-of-function mutants. Mutagenesis of predicted branchpoints reveals that the SF3B1 R625/K666 -promoted splice pattern is a direct result of alternative branchpoint usage. Altogether, this study provides a better understanding of the mechanisms underlying splicing alterations induced by mutant SF3B1 in cancer, and reveals a role for alternative branchpoints in disease.

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Rare SF3B1 R625 mutations in cutaneous melanoma

Cited by 50 publications

References 9 publications

Splicing-factor alterations in cancers

Splicing-factor alterations in cancers

The cryo-EM structure of the SF3b spliceosome complex bound to a splicing modulator reveals a pre-mRNA substrate competitive mechanism of action

Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage

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