Dr. Ann-Bin Shyu

Mechanisms Controlling Mammalian mRNA Turnover
and Their Roles in Human Disease

Our lab is interested in post-transcriptional regulation of mammalian gene expression, in particular, the role of mRNA turnover in determining the fate of cytoplasmic mRNA. One main project focuses on several critical and fundamental issues in the study of molecular mechanisms controlling mammalian mRNA decay: 1) how rapid deadenylation is triggered by RNA-destabilizing elements and how the process is regulated; 2) how, at the biochemical level, the regulation of the basic process of deadenylation, i.e., recruitment/activation of a poly(A) nuclease, impinges on mRNA turnover; 3) the directionality of exonuclease cleavage during mammalian mRNA decay and the roles the mammalian nucleases play in vivo .

In another project, we are interested in elucidating the mechanism by which mRNA decay mediated by the major protein coding-region determinant of instability (mCRD) of c- fos proto-oncogene mRNA is coupled to translation. This mechanism illustrates an extremely powerful means to achieve stringent control over transient expression of genes during cell growth and differentiation. It can be regarded as a "suicide" mechanism, in which the mRNA either remains stable but without expression into protein or gets translated and “killed” immediately via the mCRD. Ongoing efforts focus on addressing: 1) What cellular proteins mediate and/or regulate the c- fos mCRD destabilizing function? and 2) What mechanism couples mCRD mediated mRNA decay to ribosome transit during translation and how is the process controlled?

The conservation of an AU-rich RNA-destabilizing element (ARE) in the 3' non-translated regions of mRNAs coding for ~90% of cytokines and chemokines, including all type 2 helper T cells (Th2-type) cytokines, suggests that regulation of cytokine and chemokine mRNA turnover via AREs is critical in determining the duration and level of cytokine and chemokine production in various immune responses. We hypothesize that rapid decay of cytokine and chemokine mRNAs mediated by the AREs are compromised during, e.g., allergic asthma, leading to persistently high levels of cytokines and chemokines. Our efforts with this project are currently focused on: 1) developing an in vitro model to study the mechanism and regulation of chemokine and Th2-type cytokine mRNA turnover under conditions relevant to allergic responses in asthma; 2) identifying destabilizing and stabilizing ARE-binding proteins that regulate mast cell and bronchial epithelial chemokine and Th-2 type cytokine mRNA stability during allergic inflammatory responses; 3) characterizing the dynamic interplay between destabilizing and stabilizing ARE-binding proteins in regulating chemokine and cytokine mRNA levels; 4) identifying cell type(s) critical to compromised ARE-mediated RNA decay, leading to development of allergic inflammation.

Selected References

A model showing how certain nucleo-cytoplasmic shuttling proteins may participate in the ARE-mediated mRNA decay.

Lim NS, Kozlov G, Chang TC, Groover O, Siddiqui N, Volpon L, De Crescenzo G, Shyu A-B, Gehring K. Comparative peptide-binding studies of PABC domains from the E3 ubiquitin ligase HYD and poly(A)-binding protein: Implications for HYD function. J Biol Chem. 2006. (in press).

Shyu, A-B. UNRaveling the regulation of dosage compensation. Nature Struct & Mol Biol, 13: 189-190, 2006.

Yamashita, A., Chang, T-C, Yamashita, Y, Zhong, Z, Zhu, W, Chen, C-Y A, and Shyu, A-B. Concerted action of poly(A) nucleases and decapping enzyme in mammalian mRNA turnover. Nature Struct & Mol Biol, 12: 1054-1063, 2005. (*Featured in News & Views by the Journal, see pp. 1024-25)

Chang, T-C, Yamashita, A., Chen, C-Y A., Yamashita, Y, Zhu, W, Durdan, S, Kahvejian, A, Sonenberg, S, and Shyu, A-B. UNR, a new partner of poly(A)-binding protein, plays a key role in translationally coupled mRNA turnover mediated by the c-fos major coding-region determinant. Genes & Dev., 18: 2010-2023, 2004. (*Selected for Journal Research Highlights in Nature Structural and Molecular Biology, 11:811, 2004.

Chen, C-Y A, and Shyu, A-B. Rapid Deadenylation Triggered by Nonsense Codon Precedes Decay of the RNA Body in a Mammalian Cytoplasmic Nonsense-Mediated-Decay Pathway. Mol. Cell. Biol. 23: 4805-4813, 2003.

Wilkinson, M.F. and Shyu, A-B. "RNA surveillance by nuclear scanning?" Nature Cell Biol, 4: E144-E147, 2002.

Chen, C-Y A, Xu, N, and Shyu, A-B. Highly Selective Actions of HuR in Antagonizing AU-Rich Element-Mediated mRNA Destabilization. Mol. Cell. Biol. 22: 7268-7278, 2002.

Xu, N, Chen, C-Y A, Shyu, A-B. A versatile role for hnRNP D isoforms in the differential regulation of cytoplasmic mRNA turnover. Mol. Cell. Biol. 21: 6960-6971, 2001.

Grosset, C, Chen, C.-Y. A., Xu, N., Jacquemin-Sablon, H., Sonenberg, N. and Shyu, A.-B. A mechanism for translationally-coupled mRNA turnover: interaction between the poly(A) tail and an RNA stability determinant in the c-fos coding region via a novel protein complex. Cell, 103: 29-40, 2000.

Shyu, A-B. and Wilkinson, M. The double lives of shuttling RNA-binding proteins. Cell 102: 135-138, 2000.

Loflin, P. T., Chen, C.-Y. A., and Shyu, A-B. :Unraveling a cytoplasmic role for hnRNP D/AUF1 in the in vivo mRNA decay directed by the AU-rich element. Genes Dev, 13: 1884-1897, 1999.

Mechanisms Controlling Mammalian mRNA Turnover and Their Roles in Human Disease

Mechanisms Controlling Mammalian mRNA Turnover
and Their Roles in Human Disease