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Disclosing the Impact of Carcinogenic Sf3b Mutations on Pre-Mrna Recognition Via All-Atom Simulations

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Disclosing the Impact of Carcinogenic Sf3b Mutations on Pre-Mrna Recognition Via All-Atom Simulations biomolecules Article Disclosing the Impact of Carcinogenic SF3b Mutations on Pre-mRNA Recognition Via All-Atom Simulations Jure Borišek 1,2 , Andrea Saltalamacchia 3 , Anna Gallì 4 , Giulia Palermo 5, Elisabetta Molteni 6, Luca Malcovati 4,6 and Alessandra Magistrato 1,* 1 CNR-IOM-Democritos National Simulation Center c/o SISSA, 34136 Trieste, Italy; [email protected] 2 National Institute of Chemistry, 1000 Ljubljana, Slovenia 3 International School for Advanced Studies (SISSA), 34136 Trieste, Italy; [email protected] 4 Department of Hematology, IRCCS S. Matteo Hospital Foundation, 27100 Pavia, Italy; [email protected] (A.G.); [email protected] (L.M.) 5 Department of Bioengineering, University of California Riverside, Riverside, CA 92521, USA; [email protected] 6 Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy; [email protected] * Correspondence: [email protected] Received: 21 August 2019; Accepted: 17 October 2019; Published: 21 October 2019 Abstract: The spliceosome accurately promotes precursor messenger-RNA splicing by recognizing specific noncoding intronic tracts including the branch point sequence (BPS) and the 3’-splice-site (3’SS). Mutations of Hsh155 (yeast)/SF3B1 (human), which is a protein of the SF3b factor involved in BPS recognition and induces altered BPS binding and 3’SS selection, lead to mis-spliced mRNA transcripts. Although these mutations recur in hematologic malignancies, the mechanism by which they change gene expression remains unclear. In this study, multi-microsecond-long molecular-dynamics simulations of eighth distinct 700,000 atom models of the spliceosome Bact complex, and gene ∼ sequencing of SF3B1, disclose that these carcinogenic isoforms destabilize intron binding and/or affect the functional dynamics of Hsh155/SF3B1 only when binding non-consensus BPSs, as opposed to the non-pathogenic variants newly annotated here. This pinpoints a cross-talk between the distal Hsh155 mutation and BPS recognition sites. Our outcomes unprecedentedly contribute to elucidating the principles of pre-mRNA recognition, which provides critical insights on the mechanism underlying constitutive/alternative/aberrant splicing. Keywords: RNA; molecular dynamics; spliceosome; splicing 1. Introduction In eukaryotic cells, the exons, which are the coding regions of a newly transcribed precursor messenger RNA (pre-mRNA), are interspersed by non-coding regions, the introns, which have to be dismissed to produce mature mRNA before protein translation occurs. Introns removal from a nascent RNA transcript is, therefore, a pivotal step of gene expression and regulation. In eukaryotes, this process is carried out by the repeated assembly of the spliceosome (SPL), which is a majestic multi mega Dalton ribonucleic-protein machine comprising more than 100 proteins and five small nuclear RNAs (snRNAs: U1, U2, U4, U5, and U6) [1,2]. These latter congregate, through an entangled network of interactions, into five distinct small nuclear ribonucleoproteins (snRNPs), i.e., the U1, U2, U3, U4, and U5 snRNPs. The SPL processes long and diverse RNA transcripts with single nucleotide precision via the formation of eight distinct complexes, at every splicing cycle (A, B, Bact,B*, C, C*, P, and ILS). Splicing fidelity is achieved via the recognition of consensus sequences near the 50 and 30 Biomolecules 2019, 9, 633; doi:10.3390/biom9100633 www.mdpi.com/journal/biomolecules Biomolecules 2019, 9, 633 2 of 17 Biomolecules 2019, 9, 633 2 of 18 ends ofU3, introns, U4, and known U5 snRNPs. as 50 andThe SPL 30 splice processes sites long (5’SS and and diverse 3’SS, RNA respectively). transcripts with In detail,single nucleotide a conserved GU sequenceprecision at the 5’SSvia the is formation bound by of U1snRNP,eight distinct upon complexes, A complex at every assembly, splicing cycle while, (A, theB, Bact appropriate, B*, C, C*, P, 30 SS is selectedand by ILS). the U2 Splicing snRNP fidelity upon is Bachieved complex via formation. the recognition 3’SS of selection consensus takes sequences place near via the the 5 recognition′ and 3′ of short RNAends regionsof introns, such known as as the 5′ and branch 3′ splice point sites sequence (5’SS and 3’SS, (BPS), respectively). the polypyrimidine In detail, a conserved tract, and GU the AG dinucleotidesequence at theat the intron-exon 5’SS is bound junction. by U1snRNP, Among upon these A complex key sequences assembly, thewhile, BPS, the containing appropriate a3′ conservedSS is selected by the U2 snRNP upon B complex formation. 3’SS selection takes place via the recognition branching point adenosine (BPA) at the branch site (BS), is recognized by the Hsh155 (yeast)/SF3B1 of short RNA regions such as the branch point sequence (BPS), the polypyrimidine tract, and the AG act (human)dinucleotide protein in at the the Bintron-exoncomplex junction. (Figure Among1A,B). these key sequences the BPS, containing a conserved 2+ Twobranching sequential point trans-esterification adenosine (BPA) at the reactions, branch site which (BS), areis recognized mediated by by the two Hsh155 Mg (yeast)/SF3B1ions [3–5], lead to intron excision(human) protein and exon in the ligation, Bact complex promoting (Figure 1A,B). pre-mRNA maturation. Constitutive splicing occurs via snippingTwo of intronssequential and trans-esterification stitching of exons reactions, in the which same are order mediated in whichby two theyMg2+ ions appear [3–5], in lead pre-mRNA. to Alternativeintron splicing excision is,and instead, exon ligation, a divergence promoting from pre-mR thisNA preferred maturation. sequence. Constitutive In splicing this latter occurs case, via distinct snipping of introns and stitching of exons in the same order in which they appear in pre-mRNA. exons andAlternative intron /splicingexon junctions is, instead, may a divergence be alternatively from this preferred employed sequence. (i.e., In some this latter exons case, may distinct be skipped and/or intronsexons and may intron/exon be retained), junctions which may producesbe alternativ dielyfferent employed mRNA (i.e., splicingsome exons products may be fromskipped the same primaryand/or transcript introns (Figure may be1B). retained), As a result, which multipleproduces different protein isoformsmRNA splicing are created products from from a the single same gene [ 6]. The possibilityprimary andtranscript amount (Figure of alternatively 1B). As a result, spliced multiple genes protein increase isoforms with are the created complexity from a single of the gene organisms, which is[6]. the The hallmark possibility of and higher amount eukaryotes. of alternatively spliced genes increase with the complexity of the organisms, which is the hallmark of higher eukaryotes. act Figure 1.Figure(A) Intron1. (A) Intron/U2/U2 double double helix helix at at branch branch pointpoint site (BPS), (BPS), as astrapped trapped in the in B the cryo-Electron Bact cryo-Electron microscopy (EM) structure (Protein Data Bank (PDB) code 5GM6). The bulged adenine (A) at the BPS microscopy (EM) structure (Protein Data Bank (PDB) code 5GM6). The bulged adenine (A) at the BPS is is shown in van der Waals (VDW) spheres and labelled as branch point adenosine (BPA). The shown insurrounding van der Waals Hsh155, (VDW) Rds3, spheres and Ysf3 and proteins labelled are as depicted branch pointas pink, adenosine green, and (BPA). brown The cartoon surrounding Hsh155,representations, Rds3, and Ysf3 respectively. proteins Hydrogen are depicted (H)-bonds as pink, of green,base-pai andrs between brown intron cartoon and representations, U2 are respectively.highlighted Hydrogen as white (H)-bonds dashed oflines. base-pairs (B) Simplified between representation intron and of U2 constitutive are highlighted and alternative as white dashed lines. (Bsplicing.) Simplified Large representation boxes depict the of constitutiveexons, while andsmal alternativel red rectangles splicing. refer Largeto introns. boxes Constitutive depict the exons, while smallsplicing red (resulting rectangles in mRNA1) refer to is introns. schematically Constitutive presented splicing as exons (resulting ligated in the in mRNA1)same order isin schematicallywhich they appear in pre-mRNA. In alternative splicing, one pre-mRNA can be spliced in different presented as exons ligated in the same order in which they appear in pre-mRNA. In alternative splicing, transcripts (mRNA2, mRNA3), encoding for different proteins. (C) Key intron recognitions sites. BPA one pre-mRNA can be spliced in different transcripts (mRNA2, mRNA3), encoding for different proteins. at the branch site is indicated with a dark red letter. Replacement either of A to U at position -1 or of (C) KeyU intron to C at recognitions position-2 disrupts sites. BPAthe intron-U2 at the branch base-pairing, site is indicatedwhich results with in a a non-consensus dark red letter. BPS.Replacement The either ofintronic A to Usequence at position at the -15’ splicing or of U site to starts C at position-2with the highly disrupts conserved the GU intron-U2 nucleotides base-pairing, and ends at which results inthe a3’non-consensus splicing site with th BPS.e conserved The intronic AG nucleotides. sequence at the 5’ splicing site starts with the highly conserved GU nucleotides and ends at the 3’ splicing site with the conserved AG nucleotides. In order to promote alternative splicing, the SPL must recognize and process non-consensus Inintronic order to sites promote (i.e., sites alternative differing from splicing, the consen
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