期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 29, 期 6, 页码 1442-1451出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.01689-08
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资金
- Deutsche Forschungsgemeinschaft [Bi 316/10]
- Federal Ministry for Education and Research (BMBF NGNF-2 program)
- the European Commission-funded Network of Excellence EURASNET
- Fonds der Chemischen Industrie
We recently characterized human hnRNP L as a global regulator of alternative splicing, binding to CA-repeat and CA-rich elements. Here we report that hnRNP L autoregulates its own expression on the level of alternative splicing. Intron 6 of the human hnRNP L gene contains a short exon that, if used, introduces a premature termination codon, resulting in nonsense-mediated decay (NMD). This poison exon is preceded by a highly conserved CA-rich cluster extending over 800 nucleotides that binds hnRNP L and functions as an unusually extended, intronic enhancer, promoting inclusion of the poison exon. As a result, excess hnRNP L activates NMD of its own mRNA, thereby creating a negative autoregulatory feedback loop and contributing to homeostasis of hnRNP L levels. We present experimental evidence for this mechanism, based on NMD inactivation, hnRNP L binding assays, and hnRNP L-dependent alternative splicing of heterologous constructs. In addition, we demonstrate that hnRNP L cross-regulates inclusion of an analogous poison exon in the hnRNP L-like pre-mRNA, which explains the reciprocal expression of the two closely related hnRNP L proteins.
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