RNA-binding Proteins in Disease Etiology: Fragile X Syndrome and Spinal Muscular Atrophy

Overview

Journal RNA

Specialty Molecular Biology

Date 2024 Dec 18

PMID 39694825

Authors

Gideon Dreyfuss

Affiliations

Soon will be listed here.

Abstract

All RNAs exist in complexes (RNPs) with RNA-binding proteins (RBPs). Studies in my lab since the 1980s have identified, sequenced and characterized the major pre-mRNA- and mRNA-RBPs (hnRNPs/mRNPs), revealing RNA-binding domains and common features of numerous RBPs and their central roles in posttranscriptional gene regulation. The first links between RBPs and RNPs to diseases emerged serendipitously for fragile X syndrome, as its gene () encoded RBP (FMRP), and spinal muscular atrophy (SMA), caused by deficits in survival motor neurons (SMN). Discoveries of the SMN complex and its unanticipated function in RNP assembly, essential for spliceosomal snRNP biogenesis, advanced understanding of RNA biology and pathogenesis. I reflect on how these and other contributions (e.g., nucleocytoplasmic shuttling, telescripting) originated from curiosity-driven exploration and highly collaborative lab culture. The vast RNA and RBP assortments are beneficial, but increase complexity and chances of disorders, making the RNP sphere a rich source for future discoveries.

References

Choi Y, Grabowski P, Sharp P, Dreyfuss G . Heterogeneous nuclear ribonucleoproteins: role in RNA splicing. Science. 1986; 231(4745):1534-9. DOI: 10.1126/science.3952495. View

Zhang Z, Lotti F, Dittmar K, Younis I, Wan L, Kasim M . SMN deficiency causes tissue-specific perturbations in the repertoire of snRNAs and widespread defects in splicing. Cell. 2008; 133(4):585-600. PMC: 2446403. DOI: 10.1016/j.cell.2008.03.031. View

Adam S, Nakagawa T, Swanson M, Woodruff T, Dreyfuss G . mRNA polyadenylate-binding protein: gene isolation and sequencing and identification of a ribonucleoprotein consensus sequence. Mol Cell Biol. 1986; 6(8):2932-43. PMC: 367862. DOI: 10.1128/mcb.6.8.2932-2943.1986. View

FRIESEN W, Massenet S, Paushkin S, Wyce A, Dreyfuss G . SMN, the product of the spinal muscular atrophy gene, binds preferentially to dimethylarginine-containing protein targets. Mol Cell. 2001; 7(5):1111-7. DOI: 10.1016/s1097-2765(01)00244-1. View

FRIESEN W, Dreyfuss G . Specific sequences of the Sm and Sm-like (Lsm) proteins mediate their interaction with the spinal muscular atrophy disease gene product (SMN). J Biol Chem. 2000; 275(34):26370-5. DOI: 10.1074/jbc.M003299200. View

Adam S, Dreyfuss G . Adenovirus proteins associated with mRNA and hnRNA in infected HeLa cells. J Virol. 1987; 61(10):3276-83. PMC: 255908. DOI: 10.1128/JVI.61.10.3276-3283.1987. View

Matunis M, Michael W, Dreyfuss G . Characterization and primary structure of the poly(C)-binding heterogeneous nuclear ribonucleoprotein complex K protein. Mol Cell Biol. 1992; 12(1):164-71. PMC: 364080. DOI: 10.1128/mcb.12.1.164-171.1992. View

Charroux B, Pellizzoni L, Perkinson R, Yong J, Shevchenko A, Mann M . Gemin4. A novel component of the SMN complex that is found in both gems and nucleoli. J Cell Biol. 2000; 148(6):1177-86. PMC: 2174312. DOI: 10.1083/jcb.148.6.1177. View

Siomi H, Dreyfuss G . A nuclear localization domain in the hnRNP A1 protein. J Cell Biol. 1995; 129(3):551-60. PMC: 2120450. DOI: 10.1083/jcb.129.3.551. View

10.

Lefebvre S, Burlet P, Liu Q, Bertrandy S, Clermont O, Munnich A . Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet. 1997; 16(3):265-9. DOI: 10.1038/ng0797-265. View

11.

Dreyfuss G, Choi Y, Adam S . Characterization of heterogeneous nuclear RNA-protein complexes in vivo with monoclonal antibodies. Mol Cell Biol. 1984; 4(6):1104-14. PMC: 368879. DOI: 10.1128/mcb.4.6.1104-1114.1984. View

12.

Pinol-Roma S, Choi Y, Matunis M, Dreyfuss G . Immunopurification of heterogeneous nuclear ribonucleoprotein particles reveals an assortment of RNA-binding proteins. Genes Dev. 1988; 2(2):215-27. DOI: 10.1101/gad.2.2.215. View

13.

Burd C, Matunis E, Dreyfuss G . The multiple RNA-binding domains of the mRNA poly(A)-binding protein have different RNA-binding activities. Mol Cell Biol. 1991; 11(7):3419-24. PMC: 361068. DOI: 10.1128/mcb.11.7.3419-3424.1991. View

14.

Liu Q, Dreyfuss G . In vivo and in vitro arginine methylation of RNA-binding proteins. Mol Cell Biol. 1995; 15(5):2800-8. PMC: 230511. DOI: 10.1128/MCB.15.5.2800. View

15.

Roy N, Mahadevan M, McLean M, Shutler G, Yaraghi Z, Farahani R . The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell. 1995; 80(1):167-78. DOI: 10.1016/0092-8674(95)90461-1. View

16.

Pinol-Roma S, Dreyfuss G . Shuttling of pre-mRNA binding proteins between nucleus and cytoplasm. Nature. 1992; 355(6362):730-2. DOI: 10.1038/355730a0. View

17.

Charroux B, Pellizzoni L, Perkinson R, Shevchenko A, Mann M, Dreyfuss G . Gemin3: A novel DEAD box protein that interacts with SMN, the spinal muscular atrophy gene product, and is a component of gems. J Cell Biol. 1999; 147(6):1181-94. PMC: 2168095. DOI: 10.1083/jcb.147.6.1181. View

18.

Zhang Z, Pinto A, Wan L, Wang W, Berg M, Oliva I . Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy. Proc Natl Acad Sci U S A. 2013; 110(48):19348-53. PMC: 3845193. DOI: 10.1073/pnas.1319280110. View

19.

Pollard V, Michael W, Nakielny S, Siomi M, Wang F, Dreyfuss G . A novel receptor-mediated nuclear protein import pathway. Cell. 1996; 86(6):985-94. DOI: 10.1016/s0092-8674(00)80173-7. View

20.

Swanson M, Nakagawa T, Levan K, Dreyfuss G . Primary structure of human nuclear ribonucleoprotein particle C proteins: conservation of sequence and domain structures in heterogeneous nuclear RNA, mRNA, and pre-rRNA-binding proteins. Mol Cell Biol. 1987; 7(5):1731-9. PMC: 365274. DOI: 10.1128/mcb.7.5.1731-1739.1987. View