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Molecular and Cellular Biology, March 2009, p. 1442-1451, Vol. 29, No. 6
0270-7306/09/$08.00+0     doi:10.1128/MCB.01689-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Auto- and Cross-Regulation of the hnRNP L Proteins by Alternative Splicing{triangledown} ,{ddagger}

Oliver Rossbach,1,{dagger} Lee-Hsueh Hung,1,{dagger} Silke Schreiner,1,{dagger} Inna Grishina,1 Monika Heiner,1 Jingyi Hui,2 and Albrecht Bindereif1*

Institute of Biochemistry, Justus Liebig University of Giessen, Heinrich-Buff-Ring 58, D-35392 Giessen, Germany,1 State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Yue-Yang Road 320, Shanghai 200031, People's Republic of China2

Received 31 October 2008/ Returned for modification 8 December 2008/ Accepted 23 December 2008

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.

* Corresponding author. Mailing address: Institute of Biochemistry, Justus-Liebig-University of Giessen, Heinrich-Buff-Ring 58, D-35392 Giessen, Germany. Phone: 49-641-9935 420. Fax: 49-641-9935 419. E-mail: albrecht.bindereif{at}chemie.bio.uni-giessen.de

{triangledown} Published ahead of print on 5 January 2009.

{ddagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{dagger} O.R., L.-H.H., and S.S. contributed equally to this study.

Molecular and Cellular Biology, March 2009, p. 1442-1451, Vol. 29, No. 6
0270-7306/09/$08.00+0     doi:10.1128/MCB.01689-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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