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Minor spliceosome catalytic core unveiled

Mariia V. Shcherbii , Anqi Peng , Mikko J. Frilander

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Vita > Cutting Edge > DOI: 10.15302/vita.2026.06.0041
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Minor spliceosome catalytic core unveiled

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In a recent study in Vita, Bai et al.1 present 2.9–3.0 Å cryo-EM structures of the human minor spliceosome in its two catalytic states — the branching-completed C and exon-ligation-ready C* states — revealing the active-site architecture during minor intron splicing. The study shows how four previously uncharacterized minor-spliceosome-specific proteins MMTAG2, WDR25, FAM204A, and RBM41 coordinate and safeguard the two catalytic steps of intron removal, and further uncovers intriguing connections between minor spliceosome activity and the regulation of cell growth.

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The landmark discovery 30 years ago revealed that most metazoans, including humans, possess two parallel pre-mRNA splicing machineries2,3. This discovered machinery, the minor spliceosome, immediately raised fundamental questions about its composition, architecture, assembly pathway, and regulatory significance. In this issue of Vita, Bai et al.1 now report the structural characterization of the two key assembly intermediates needed to understand the minor spliceosome catalytic steps, answering many of the original questions and setting the stage for future work.
Both the minor and major spliceosomes are massive, dynamic molecular machines that recognize and excise noncoding introns from pre-mRNA and then join the coding exons to form functional mRNAs. Pre-mRNA splicing utilizes five small nuclear ribonucleoproteins (snRNPs), composed of small nuclear RNAs (snRNAs) and associated protein components. Together with numerous transiently acting protein components, the snRNPs participate in a stepwise spliceosome assembly which starts with intron recognition and the formation of catalytically active spliceosome, followed by two catalytic steps of splicing, and ends with spliceosome disassembly4 (Fig. 1a). For the major spliceosome, which recognizes the bulk of the introns (> 200,000 in humans), the atomic-level details of the entire assembly–disassembly cycle have been defined4. In contrast, structural characterization of the minor spliceosome, which excises a small subset of introns (~750 in humans), has been more challenging. A key difficulty likely stems from the 50–100× lower cellular abundance of minor-spliceosome-specific snRNAs, which can limit the efficiency of in vitro splicing reactions. Bai et al. overcome these limitations through careful optimization of in vitro splicing conditions, enabling the production of catalytically relevant complexes in sufficient quantities and purity for high-resolution cryo-EM analysis. They report 2.9–3.0 Å structures of the catalytic C and C* complexes that have undergone the first, but not the second step of splicing. Together with previously reported high-resolution structures of U11 snRNP, pre-B, and Bᵃᶜᵗ complexes from earlier assembly stages5-7 (Fig. 1a), this work completes two key missing steps of the minor intron splicing process, revealing similarities and differences between the major and minor spliceosomes.
From the structural perspective, this work reveals the conserved architectural features shared by the minor and major spliceosome complexes C and C* and uncovers the distinct structural adaptations specific to the minor spliceosome. Most importantly, the catalytic RNA core of the minor spliceosome closely mirrors that of the major spliceosome. The two key minor spliceosome snRNAs, U12 and U6atac, are base-paired and adopt a configuration nearly identical to the major spliceosome U2/U6 catalytic center and coordinate the catalytic metal ions in a highly conserved manner. This reinforces earlier biochemical, genetic, and structural data indicating that despite their distinct snRNA compositions, the major and minor spliceosomes employ a fundamentally conserved catalytic strategy. A further highlight is the identification of four novel minor-spliceosome-specific proteins: one (MMTAG2) in the C complex and three (RBM41, WDR25, and FAM204A) in the C* complex, which stabilize the active site conformation. This finding is consistent with earlier structural studies that identified unique minor-spliceosome-specific proteins in each assembly intermediate5-7. Collectively, these structural studies support the general conclusion8 that unique minor-spliceosome-specific proteins are particularly needed to compensate for RNA sequence-level and structural changes resulting from the use of divergent snRNAs in the two spliceosomes.
Beyond their structural roles, the newly identified minor-spliceosome-specific proteins in C and C* complexes provide support for the present view of the minor spliceosome as a regulator of cellular growth and proliferation. Specifically, multiple studies suggest that the minor spliceosome is a limiting factor in processing many growth-associated transcripts and plays a role in cancer progression. For example, elevated U6atac snRNA levels have been shown to promote disease progression in castration-resistant prostate cancer9, while loss of the minor-spliceosome-specific protein ZRSR2 leads to a myelodysplastic syndrome that can progress to acute myeloid leukemia10. Of the four novel proteins, two C* complex proteins (WDR25 and FAM204A) have been used as prognostic markers in carcinomas, while the C-complex protein MMTAG2 (also known as C1orf35) has an even more direct connection to cancer. It has previously been described as a transcriptional activator linked to cell-cycle progression that directly promotes c-MYC expression in multiple myeloma cells11. The identification of MMTAG2 in the minor spliceosome raises the possibility that it is a dual-function protein, acting as both a transcriptional activator and a spliceosome component. If this holds true, it raises the intriguing possibility of concerted control of c-MYC at both transcriptional and post-transcriptional levels (Fig. 1b). Given that a substantial fraction of minor-spliceosome target genes have functions associated with cellular growth 8, the hypothetical dual functionality of MMTAG2 could enable concerted control of this process in healthy cells, and its deregulation in cancer.
Looking ahead, the new high-resolution structures bring the minor spliceosome close to structural parity with the major spliceosome for the catalytic phase, yet important gaps remain (Fig. 1a). High-resolution structures of the earliest assembly intermediates and of the post-catalytic disassembly states are still missing. Without these structures, the complete minor-spliceosome cycle cannot yet be compared step by step with that of the major spliceosome. Nevertheless, the available structures have already provided mechanistic insight into not only this biological process but also into many human hereditary diseases caused by loss-of-function mutations in the minor spliceosome8. The strong association of several minor-spliceosome components with various cancers, suggests that minor-spliceosome activity may regulate many growth-associated genes, providing a possible means to control cancer cell growth. By defining the catalytic site and the accessory proteins, Bai et al.’s work provides a structural framework for probing how the minor spliceosome could function as a rate-limiting checkpoint and thus paves the way for potential therapeutic strategies.

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The Author(s) 2026. Published by Higher Education Press. This is an Open Access article distributed under the terms of the CC BY license (https://creativecommons.org/licenses/by/4.0/).

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Shcherbii, M., Peng, A., Frilander, M. Minor spliceosome catalytic core unveiled Vita https://doi.org/10.15302/vita.2026.06.0041 ()
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