Figure 1.
RNA splicing catalysis, splicing regulation, and location of splicing factors mutated in hematologic malignancies in the splicing process. (A) Sequences embedded within premature RNA serve to recruit the spliceosome and include the 5' and 3' splice sites (which are most commonly GU and AG dinucleotides, respectively), the BPS, and polypyrimidine (poly Y) tract. The branch-point nucleotide is most commonly an adenosine nucleotide as shown, but other nucleotides can occasionally serve as branch points, and it is not uncommon for introns to have multiple branch points. (B) Although splicing requires several hundred proteins, the core steps of splicing catalysis consist of 2 sequential transesterification reactions as shown. RNA splicing is initiated when the branch nucleotide performs a nucleophilic attack of the 5'ss, resulting in the formation of an intron lariat intermediate with a 2', 5'-phosphodiester linkage. This is followed by a 5'ss-mediated attack on the 3'ss, leading to the removal of the intron lariat and the formation of the spliced RNA product. (C) The enzymatic steps of splicing are carried out by groups of proteins complexed with snRNAs termed snRNPs. Factors labeled in red in this diagram under recurrent mutations in patients with hematologic malignancies. Splicing is initiated with binding of the U1 snRNP binds the 5'ss, SF1 to the BPS, (iii) U2AF2 to the polypyrimidine tract, and (iv) U2AF1 to the 3ss. These interactions enhance recruitment of U2 snRNP to the BPS. SF3B1, a component of U2 snRNP, is involved in the binding to the BPS. The preassembled U4/U6.U5 tri-snRNP complex joins and the U1/U4 snRNPs are released to form a catalytically active complex of the spliceosome, which catalyze the first and second esterification reactions, respectively, and mediate excision of the intron and ligation of the proximal and distal exon to synthesize mature mRNA. (D) Beyond splice sites, BPS, and the poly Y tract, additional sequences located within introns and exons serve to recruit auxiliary splicing factors, that interact with the spliceosome and promote or repress spliceosome function. These are termed ESEs or exonic splicing silencers (ESSs), respectively) or intronic splicing enhancers or silencers (ISEs or ISSs, respectively). Splicing regulatory proteins known as SR or hnRNP proteins most commonly enhance or repress spliceosome recruitment, respectively, as illustrated.

RNA splicing catalysis, splicing regulation, and location of splicing factors mutated in hematologic malignancies in the splicing process. (A) Sequences embedded within premature RNA serve to recruit the spliceosome and include the 5' and 3' splice sites (which are most commonly GU and AG dinucleotides, respectively), the BPS, and polypyrimidine (poly Y) tract. The branch-point nucleotide is most commonly an adenosine nucleotide as shown, but other nucleotides can occasionally serve as branch points, and it is not uncommon for introns to have multiple branch points. (B) Although splicing requires several hundred proteins, the core steps of splicing catalysis consist of 2 sequential transesterification reactions as shown. RNA splicing is initiated when the branch nucleotide performs a nucleophilic attack of the 5'ss, resulting in the formation of an intron lariat intermediate with a 2', 5'-phosphodiester linkage. This is followed by a 5'ss-mediated attack on the 3'ss, leading to the removal of the intron lariat and the formation of the spliced RNA product. (C) The enzymatic steps of splicing are carried out by groups of proteins complexed with snRNAs termed snRNPs. Factors labeled in red in this diagram under recurrent mutations in patients with hematologic malignancies. Splicing is initiated with binding of the U1 snRNP binds the 5'ss, SF1 to the BPS, (iii) U2AF2 to the polypyrimidine tract, and (iv) U2AF1 to the 3ss. These interactions enhance recruitment of U2 snRNP to the BPS. SF3B1, a component of U2 snRNP, is involved in the binding to the BPS. The preassembled U4/U6.U5 tri-snRNP complex joins and the U1/U4 snRNPs are released to form a catalytically active complex of the spliceosome, which catalyze the first and second esterification reactions, respectively, and mediate excision of the intron and ligation of the proximal and distal exon to synthesize mature mRNA. (D) Beyond splice sites, BPS, and the poly Y tract, additional sequences located within introns and exons serve to recruit auxiliary splicing factors, that interact with the spliceosome and promote or repress spliceosome function. These are termed ESEs or exonic splicing silencers (ESSs), respectively) or intronic splicing enhancers or silencers (ISEs or ISSs, respectively). Splicing regulatory proteins known as SR or hnRNP proteins most commonly enhance or repress spliceosome recruitment, respectively, as illustrated.

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