RNA-binding proteins RBM20 and PTBP1 regulate the alternative splicing of FHOD3

Lorenzi, Pamela; Fochi, Stefania; Molin, Anna Dal; Malerba, Giovanni; Zipeto, Donato

doi:10.1016/j.biocel.2018.11.009

Cited by 19 publications

(19 citation statements)

References 75 publications

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“…has been found to co-regulate splicing with RBM20 for FHOD3 pre-mRNA (Lorenzi et al, 2019), and also for a mini-gene reporter based on titin . Given the similarity in UCUU binding mechanisms between RBM20 and RRM1 of PTBP1 (Fig.…”

Section: In Terms Of Protein-protein Interactions Polypyrimidine Tramentioning

confidence: 99%

“…Human, rat and mouse studies identified additional splicing targets that encode proteins which bind and transport Ca 2+ (Guo et al, 2012;van den Hoogenhof et al, 2018;Guo et al, 2018;Maatz et al, 2014;Wyles et al, 2016;Beraldi et al, 2014) such as the calcium channel ryanodine receptor 2 (RYR2), Ca 2+ /calmodulin-dependent protein kinase II delta (CAMK2δ), and the calcium channel voltage-gated L type alpha 1C subunit (CACNA1C/Cav1.2). Other characterized targets include formin homology 2 domain containing 3 (FHOD3), Z-band alternatively spliced PDZ-motif protein (ZASP/LDB3/CYPHER), and the PDZ and LIM domain protein 5 (PDLIM5/ENH) (Maatz et al, 2014;Guo et al, 2012;Lorenzi et al, 2019;Ito et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Structural basis of UCUU RNA motif recognition by splicing factor RBM20

Upadhyay

Mackereth

2019

Preprint

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The vertebrate splicing factor RBM20 (RNA Binding Motif protein 20) regulates protein isoforms important for heart development and function, with mutations in the gene linked to cardiomyopathy. Previous studies have identified the four base RNA motif UCUU as a common element in pre-mRNA targeted by RBM20. Here, we have determined the structure of the RNA Recognition Motif (RRM) domain from mouse RBM20 bound to RNA containing a UCUU sequence. The atomic details show that the RRM domain spans a larger region than initially proposed in order to interact with the complete UCUU motif, with a well-folded Cterminal helix encoded by exon 8 critical for high affinity binding. This helix only forms upon binding RNA with the final uracil, and removing the helix reduces affinity as well as specificity. We therefore find that RBM20 uses a coupled folding-binding mechanism by the C-terminal helix to specifically recognize the UCUU RNA motif.

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Section: In Terms Of Protein-protein Interactions Polypyrimidine Tramentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structural basis of UCUU RNA motif recognition by splicing factor RBM20

Upadhyay

Mackereth

2019

Preprint

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“…Furthermore, we observed a positive correlation between FHOD3 exon 12 skipping and the overexpression of RBM20 or PTBP1. We hypothesize that they both participate in the splice site recognition by competing with the snRNP spliceosomal components that determine the exon inclusion/exclusion outcome [32].…”

Section: Rbm20 and Ptbp1 Combinatorial Effects On Alternative Splicingmentioning

confidence: 99%

“…Based on recent studies, novel evidences have highlighted the role of the well-known splicing regulator polypyrimidine-tract binding protein 1 (PTBP1) in the regulation of alternatively spliced variants that are critical for the heart functionality [31,32]. In this review, we summarize the functional evidences of the role of RBM20 in the regulation of TTN and additional genes involved in heart function and cardiac diseases development.…”

Section: Introductionmentioning

confidence: 99%

The Emerging Role of the RBM20 and PTBP1 Ribonucleoproteins in Heart Development and Cardiovascular Diseases

Fochi

Lorenzi

Galasso

et al. 2020

Genes

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Alternative splicing is a regulatory mechanism essential for cell differentiation and tissue organization. More than 90% of human genes are regulated by alternative splicing events, which participate in cell fate determination. The general mechanisms of splicing events are well known, whereas only recently have deep-sequencing, high throughput analyses and animal models provided novel information on the network of functionally coordinated, tissue-specific, alternatively spliced exons. Heart development and cardiac tissue differentiation require thoroughly regulated splicing events. The ribonucleoprotein RBM20 is a key regulator of the alternative splicing events required for functional and structural heart properties, such as the expression of TTN isoforms. Recently, the polypyrimidine tract-binding protein PTBP1 has been demonstrated to participate with RBM20 in regulating splicing events. In this review, we summarize the updated knowledge relative to RBM20 and PTBP1 structure and molecular function; their role in alternative splicing mechanisms involved in the heart development and function; RBM20 mutations associated with idiopathic dilated cardiovascular disease (DCM); and the consequences of RBM20-altered expression or dysfunction. Furthermore, we discuss the possible application of targeting RBM20 in new approaches in heart therapies.

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“…Another RRM family protein, RBM20, is a tissue‐specific pre‐mRNA splicing factor that is highly expressed in human heart. RBM20 mediates the alternative splicing of specific mRNA variants of many genes in cardiac muscles . Mutations in Rbm20 gene are reported to be related with dilated cardiomyopathy in humans …”

Section: Introductionmentioning

confidence: 99%