Regulation of pre-mRNA splicing: roles in physiology and disease, and therapeutic prospects

Irimia, M. & Roy, S. W. Origin of spliceosomal introns and alternative splicing. Cold Spring Harb. Perspect. Biol. 6, a016071 (2014).

Article  Google Scholar 

Plaschka, C., Newman, A. J. & Nagai, K. Structural basis of nuclear pre-mRNA splicing: lessons from yeast. Cold Spring Harb. Perspect. Biol. 11, a032391 (2019).

Article  CAS  Google Scholar 

Wan, R., Bai, R., Yan, C., Lei, J. & Shi, Y. Structures of the catalytically activated yeast spliceosome reveal the mechanism of branching. Cell 177, 339–351 (2019).

Article  CAS  Google Scholar 

Kastner, B., Will, C. L., Stark, H. & Lührmann, R. Structural insights into nuclear pre-mRNA splicing in higher eukaryotes. Cold Spring Harb. Perspect. Biol. 11, a032417 (2019).

Article  CAS  Google Scholar 

Tholen, J. & Galej, W. P. Structural studies of the spliceosome: bridging the gaps. Curr. Opin. Struct. Biol. 77, 102461 (2022).

Article  CAS  Google Scholar 

Wahl, M. C., Will, C. L. & Lührmann, R. The spliceosome: design principles of a dynamic RNP machine. Cell 136, 701–718 (2009).

Article  CAS  Google Scholar 

Turunen, J. J., Niemelä, E. H., Verma, B. & Frilander, M. J. The significant other: splicing by the minor spliceosome. Wiley Interdiscip. Rev. RNA 4, 61–76 (2013).

Article  CAS  Google Scholar 

Pan, Q., Shai, O., Lee, L. J., Frey, B. J. & Blencowe, B. J. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat. Genet. 40, 1413–1415 (2008).

Article  CAS  Google Scholar 

Wang, E. T. et al. Alternative isoform regulation in human tissue transcriptomes. Nature 456, 470–476 (2008).

Article  CAS  Google Scholar 

Nilsen, T. W. & Graveley, B. R. Expansion of the eukaryotic proteome by alternative splicing. Nature 463, 457–463 (2010).

Article  CAS  Google Scholar 

Baralle, F. E. & Giudice, J. Alternative splicing as a regulator of development and tissue identity. Nat. Rev. Mol. Cell Biol. 18, 437–451 (2017).

Article  CAS  Google Scholar 

Zavolan, M. & Kanitz, A. RNA splicing and its connection with other regulatory layers in somatic cell reprogramming. Curr. Opin. Cell Biol. 52, 8–13 (2018).

Article  CAS  Google Scholar 

Scotti, M. M. & Swanson, M. S. RNA mis-splicing in disease. Nat. Rev. Genet. 17, 19–32 (2016).

Article  CAS  Google Scholar 

Manning, K. S. & Cooper, T. A. The roles of RNA processing in translating genotype to phenotype. Nat. Rev. Mol. Cell Biol. 18, 102–114 (2017).

Article  CAS  Google Scholar 

Wright, C. J., Smith, C. W. J. & Jiggins, C. D. Alternative splicing as a source of phenotypic diversity. Nat. Rev. Genet. 23, 697–710 (2022).

Article  CAS  Google Scholar 

Gebauer, F., Schwarzl, T., Valcárcel, J. & Hentze, M. W. RNA-binding proteins in human genetic disease. Nat. Rev. Genet. 22, 185–198 (2021).

Article  CAS  Google Scholar 

Finkel, R. S. et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N. Engl. J. Med. 377, 1723–1732 (2017). This study provides evidence for the clinical benefit of splicing modulation in the treatment of a human genetic disorder.

Article  CAS  Google Scholar 

Bonnal, S. C., López-Oreja, I. & Valcárcel, J. Roles and mechanisms of alternative splicing in cancer — implications for care. Nat. Rev. Clin. Oncol. 17, 457–474 (2020).

Article  Google Scholar 

Shen, H. et al. Mouse totipotent stem cells captured and maintained through spliceosomal repression. Cell 184, 2843–2859 (2021). This study reveals an unexpected link between splicing activity and cell totipotency, with potential applications in regenerative medicine.

Article  CAS  Google Scholar 

To, K. K. W. & Cho, W. C. S. An overview of rational design of mRNA-based therapeutics and vaccines. Expert. Opin. Drug. Discov. 16, 1307–1317 (2021).

Article  CAS  Google Scholar 

Black, D. L. Finding splice sites within a wilderness of RNA. RNA 1, 763–771 (1995).

CAS  Google Scholar 

Lu, S. X. et al. Pharmacologic modulation of RNA splicing enhances anti-tumor immunity. Cell 184, 4032–4047 (2021). This study illustrates the potential of splicing inhibitors to enhance the generation of neoantigens expressed in cancer cells.

Article  CAS  Google Scholar 

Kondo, Y., Oubridge, C., van Roon, A. M. M. & Nagai, K. Crystal structure of human U1 snRNP, a small nuclear ribonucleoprotein particle, reveals the mechanism of 5’ splice site recognition. eLife 4, 1–19 (2015).

Article  Google Scholar 

Slaugenhaupt, S. A. et al. Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am. J. Hum. Genet. 68, 598–605 (2001).

Article  CAS  Google Scholar 

Dietrich, P. & Dragatsis, I. Familial dysautonomia: mechanisms and models. Genet. Mol. Biol. 39, 497–514 (2016).

Article  CAS  Google Scholar 

Shuai, S. et al. The U1 spliceosomal RNA is recurrently mutated in multiple cancers. Nature 574, 712–716 (2019).

Article  CAS  Google Scholar 

Suzuki, H. et al. Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma. Nature 574, 707–711 (2019). Shuai et al. and Suzuki et al. show that mutations in snRNAs can promote cancer progression.

Article  CAS  Google Scholar 

Roca, X. & Krainer, A. R. Recognition of atypical 5′ splice sites by shifted base-pairing to U1 snRNA. Nat. Struct. Mol. Biol. 16, 176–182 (2009).

Article  CAS  Google Scholar 

Roca, X. et al. Widespread recognition of 5′ splice sites by noncanonical base-pairing to U1 snRNA involving bulged nucleotides. Genes. Dev. 26, 1098–1109 (2012).

Article  CAS  Google Scholar 

Roca, X., Krainer, A. R. & Eperon, I. C. Pick one, but be quick: 5′ splice sites and the problems of too many choices. Genes. Dev. 27, 129–144 (2013).

Article  CAS  Google Scholar 

Wong, M. S., Kinney, J. B. & Krainer, A. R. Quantitative activity profile and context dependence of all human 5′ splice sites. Mol. Cell 71, 1012–1026.e3 (2018). This study presents a systematic assessment of the activity and context dependence of sequence variation at 5’ splice sites.

Article  CAS  Google Scholar 

Aznarez, I. et al. A systematic analysis of intronic sequences downstream of 5′ splice sites reveals a widespread role for U-rich motifs and TIA1/TIAL1 proteins in alternative splicing regulation. Genome Res. 18, 1247–1258 (2008).

Article  CAS  Google Scholar 

Yu, Y. et al. Dynamic regulation of alternative splicing by silencers that modulate 5′ splice site competition. Cell 135, 1224–1236 (2008).

Article  CAS  Google Scholar 

Plaschka, C., Lin, P. C., Charenton, C. & Nagai, K. Prespliceosome structure provides insights into spliceosome assembly and regulation. Nature 559, 419–422 (2018).

Article  CAS  Google Scholar 

Jourdain, A. A. et al. Loss of LUC7L2 and U1 snRNP subunits shifts energy metabolism from glycolysis to OXPHOS. Mol. Cell 81, 1905–1919 (2021).

Article  CAS  Google Scholar 

Singh, N. N., Singh, R. N. & Androphy, E. J. Modulating role of RNA structure in alternative splicing of a critical exon in the spinal muscular atrophy genes. Nucleic Acids Res. 35, 371–389 (2007).

Article  CAS  Google Scholar 

Hua, Y. et al. Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature 478, 123–126 (2011).

Article  CAS  Google Scholar 

Jha, N. N., Kim, J. K. & Monani, U. R. Motor neuron biology and disease: a current perspective on infantile-onset spinal muscular atrophy. Future Neurol. 13, 161–172 (2018).

Article  CAS  Google Scholar 

Albrechtsen, S. S., Born, A. P. & Boesen, M. S. Nusinersen treatment of spinal muscular atrophy — a systematic review. Dan. Med. J. 67, 1–12 (2020).

Google Scholar 

Ratni, H. et al. Discovery of risdiplam, a selective survival of motor neuron-2 (SMN2) gene splicing modifier for the treatment of spinal muscular atrophy (SMA). J. Med. Chem. 61, 6501–6517 (2018).

Article  CAS  Google Scholar 

Darras, B. T. et al. Risdiplam-treated infants with type 1 spinal muscular atrophy versus historical controls. N. Engl. J. Med. 385, 427–435 (2021).

Article  CAS  Google Scholar 

Campagne, S. et al. Structural basis of a small molecule targeting RNA for a specific splicing correction. Nat. Chem. Biol. 15, 1191–1198 (2019). This study provides the molecular rationale for the specific effects of a small molecule modulator of 5’ splice recognition.

Article  CAS  Google Scholar 

Singh, R. N., Seo, J. & Singh, N. N. RNA in spinal muscular atrophy: therapeutic implications of targeting. Expert. Opin. Ther. Targets 24, 731–743 (2020).

Article  CAS  Google Scholar 

Alanis, E. F. et al. An exon-specific U1 small nuclear RNA (snRNA) strategy to correct splicing defects. Hum. Mol. Genet. 21, 2389–2398 (2012).

Article  Google Scholar 

Rogalska, M. E. et al. Therapeutic activity of modified U1 core spliceosomal particles. Nat. Commun. 7, 11168 (2016).

Article  CAS  Google Scholar 

Donegà, S. et al. Rescue of common exon-skipping mutations in cystic fibrosis with modified U1 snRNAs. Hum. Mutat. 41, 2143–2154 (2020).

Article  Google Scholar 

留言 (0)

沒有登入
gif