PROFESSOR JAVIER CACERES
Chromosomes and Gene Expression
|Telephone:||+44 (0)131 332 2471 (extension 2301)|
|Fax:||+44 (0)131 467 8456|
|Address:||MRC Human Genetics Unit MRC IGMM, University of Edinburgh Western General Hospital, Crewe Road, Edinburgh EH4 2XU|
|Research Programme:||RNA Processing in Eukaryotes|
RNA Processing in Eukaryotes
Gene expression is extensively regulated at the post-transcriptional level. The fundamental steps of eukaryotic RNA processing have been characterised in great detail, but knowledge of how the disruption of these processes contributes to human disease has only recently begun to emerge. The major aim of this programme is to study the mechanisms for the post-transcriptional regulation of gene expression in health and disease. Our laboratory studies different aspects of RNA processing, including alternative splicing regulation, nonsense-mediated decay (NMD) and microRNA (miRNA) biogenesis.
We are particularly interested in the trans-acting factors that regulate alternative splicing, such as the SR proteins and hnRNP A/B type of proteins. These proteins have antagonistic activities and their molar ratio influence different modes of alternative splicing in vivo and may represent a mechanism for tissue-specific or developmental regulation of gene expression. We also study the subcellular distribution of RNA processing factors and how this could be affected by extracellular signals. More recently, we have uncovered functions for splicing factors in the regulation of translation.
MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate the expression of complementary mRNAs and affect a great diversity of biological processes. Their biogenesis involves a nuclear phase catalyzed by the Microprocessor (Drosha/DGCR8) followed by a cytoplasmic step carried out by Dicer to produce the mature miRNA. We have shown that hnRNP A1, a protein implicated in many aspects of RNA processing, promotes the Drosha-mediated processing of a miRNA precursor, pri-miR-18a, by binding to its conserved terminal loop. By contrast, hnRNP A1 is a negative regulator of Let-7a in differentiated cells by antagonizing the positive role of the KH-type splicing regulatory protein KSRP. Altogether, these data suggest the existence of auxiliary factors for the processing of specific miRNAs that can have a positive or negative role in the production of individual miRNAs.
- Choudhury NR, de Lima AF, de Andres-Aguayo L, Graf T, Caceres JF, Rappsilber J, and Michlewski G. Tissue-specific control of brain-enriched miR-7 biogenesis. Genes Dev. 27: 24-38. 2013
- Macias S, Plass M, Stajuda A, Michlewski G, Eyras E, Caceres JF: DGCR8 HITS-CLIP reveals novel functions for the Microprocessor
Nat Struct Mol Biol 19:760-766, 2012.
- Anastasaki, C., Longman, D., Capper, A., Patton, E.E. and Cáceres,J.F. (2011) Dhx34 and Nbas function in the NMD pathway and are required for embryonic development in zebrafish. Nucleic Acids Res, [Epub ahead of print]. PubMed Abstract
- Michlewski, G. and Cáceres, J.F. Antagonistic role of hnRNP A1 and KSRP in the regulation of Let-7a biogenesis. Nat. Struct. Mol. Biol. 17 (8) 1011-1018, 2010. PubMed Abstract
- Michlewski, G. and Cáceres, J.F. RNase-assisted RNA chromatography. RNA 16 (8) 1673-1678, 2010. PubMed Abstract
- Ellis, J.D.; Lleres, D.; Denegri, M.; Lamond, A.I. and Cáceres, J.F. Spatial mapping of splicing factor complexes involved in exon and intron definition. Journal of Cell Biology 181(6):921-934, 2008. PubMed Abstract
- Guil, S. and Cáceres, J.F. The multifunctional RNA-binding protein hnRNP A1 is required for processing of miR-18a. Nat. Struct. Mol. Biol. 14 (7): 591-596, 2007. PubMed Abstract
- Longman,D.; Plasterk,R.H.; Johnstone,I.L. and Cáceres, J.F. Mechanistic insights and identification of two novel factors in the C. elegans NMD pathway. Genes Dev. 21 (9): 1075-1085, 2007. PubMed Abstract
Sanford,J.R., Ellis,J., Cazalla,D. and Cáceres,J.F. Reversible phosphorylation differentially affects nuclear and cytoplasmic functions of splicing factor 2/alternative splicing factor. Proc. Natl. Acad. Sci. USA. 102 (42): 15042-15047, 2005. PubMed Abstract
Sanford,J.R., Gray,N.K., Beckmann,K. and Cáceres,J.F. A novel role for shuttling SR proteins in mRNA translation. Genes Dev. 18 (7): 755-768, 2004. PubMed Abstract
Longman,D., Johnstone,I.L. and Cáceres,J.F. Functional characterization of SR and SR related genes in Caenorhabditis elegans. EMBO J. 19 (7)1625-1637, 2000. PubMed Abstract
v.d. Houven van Oordt,W., Diaz-Meco,M.T., Lozano,J., Krainer,A.R., Moscat,J. and Cáceres,J.F. The MKK3/6-p38 signaling cascade alters the subcellular distribution of hnRNP A1 and modulates alternative splicing regulation. J. Cell Biol., 149 (2): 307-316, 2000. PubMed Abstract
Long, J.C. and Cáceres, J.F. The SR protein family of splicing factors: master regulators of gene expression. Biochem. J. 417 (1) 15-27, 2009. PubMed Abstract