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Recognition of the 5' splice site by the spliceosome

100%

Konarska M. M.

Acta Biochimica Polonica

1998

tom 45

nr 4

The splicing of nuclear pre-mRNAs is catalyzed by a large, multicomponent ribonucleoprotein complex termed the spliceosome. Elucidation of the molecular mechanism of splicing identified small nuclear RNAs (snRNAs) as important components of the spliceosome, which, by analogy to the self-splicing group II introns, are implicated in formation of the catalytic center. In particular, the 5' splice site (5'SS) and the branch site, which represent the two substrates for the first step of splicing, are first recognized by U1 and U2 snRNPs, respectively. This initial recognition of splice sites is responsible for the global definition of exons and introns, and represents the primary target for regulation of splicing. Subsequently, pairing interaction between the 5'SS and U1 snRNA is disrupted and replaced by a new interaction of the 5'SS with U6 snRNA. The 5'SS signal contains an invariant GU dinucleotide present at the 5' end of nearly all known introns, however, the mechanism by which the spliceosome recognizes this element is not known. We have identified and characterized a specific UV light-induced crosslink formed between the 5'SS RNA and hPrp8, a protein component of U5 snRNP in the spliceosome that is likely to reflect a specific recognition of the GU dinucleotide for splicing. Because recognition of the 5'SS must be linked to formation of the catalytic site, the identification of a specific and direct interaction between the 5'SS and Prp8 has significant implications for the role of this protein in the mechanism of mRNA splicing.

Emerging role of alternative splicing of CRF1 receptor in CRF signaling

84%

Zmijewski M. A., Slominski A. T.

Acta Biochimica Polonica

2010

tom 57

nr 1

1-13

Alternative splicing of mRNA is one of the most important mechanisms responsible for an increase of the genomic capacity. Thus the majority of human proteins including G protein-coupled receptors (GPCRs) possess several isoforms as a result of mRNA splicing. The corticotropin-releasing factor (CRF) and its receptors are the most proximal elements of hypothalamic-pituitary-adrenal axis (HPA) - the central machinery of stress response. Moreover, expression of CRF and regulated activity of CRF receptor type 1 (CRF1) can also play an important role in regulation of local stress response in peripheral tissues including skin, gastrointestinal tract or reproductive system. In humans, expression of at least eight variants of CRF1 mRNA (α, β, c, d, e, f, g and h) was detected and alternative splicing was found to be regulated by diverse physiological and pathological factors including: growth conditions, onset of labor, during pregnancy or exposure to ultraviolet irradiation. The pattern of expression of CRF1 isoforms is cell type specific and recently has been linked to observed differences in responsiveness to CRF stimulation. In the proposed model of regulation of CRF-signaling, isoform CRF1α plays a central role. Other isoforms modulate its activity by oligomerization, leading to alteration in receptor trafficking, localization and function. Co-expression of CRF1 isoforms modulates sensitivity of cells to the ligands and influences downstream coupling to G-proteins. The other possible regulatory mechanisms include fast mRNA and/or protein turnover or decoy receptor function of CRF1 isoforms. Taken together, alternative splicing of CRF1 can represent another level of regulation of CRF-mediated stress responses at the central and peripheral levels. Chronic stress or malfunction of the HPA-axis have been linked to numerous human pathologies, suggesting that alternative splicing of CRF1 receptor could represent a promising target for drugs development.

Ograniczanie wyników

2 Acta Biochimica Polonica

1 Konarska M. M.

1 Slominski A. T.

1 Zmijewski M. A.

1 2010

1 1998

Wyniki wyszukiwania

Recognition of the 5' splice site by the spliceosome

Emerging role of alternative splicing of CRF1 receptor in CRF signaling