|During my PhD I studied the alternative splicing pathways of CD44 in human breast cells, showing that one of these pathways is de-regulated in ductal carcinomas. I then performed my post-doctoral research in Adrian R. Krainer Lab at Cold Spring Harbor Laboratory, New York (USA). There I investigated the basic mechanisms of 5' splice-site selection in humans using a combination of molecular, genomic and computational approaches. I also functionally characterized splicing mutations causing various genetic diseases, such as metabolic, neurological and muscular disorders. My major finding is the unexpected flexibility in the recognition of 5' splice sites by the U1 small nuclear RNA, which challenged a long-standing dogma and holds important implications for disease-causing splicing mutations and alternative splicing.|
|My research focuses on the study of the mechanisms of pre-messenger RNA splicing in human cells. Splicing is the process by which introns are excised and exons are joined together, and is essential for the correct expression of genes. The relevance of splicing in the big picture is further illustrated by these two facts: (1) a large fraction (~50%) of point mutations causing human hereditary disease and cancer affect splicing, and other syndromes are caused by alterations of splicing factors; (2) alternative splicing affects >90% of genes in the human genome, is critical to explain the complexity of the human transcriptome and proteome, and contributes to many processes at a cellular and organismal level. The molecular and phenotypic consequences of many disease-causing mutations at splicing elements are not predictable at present, and the mechanisms of alternative splicing and their impact on other biological processes are still largely unknown. These limitations stress the need to further understand the basic mechanisms of splicing. In my lab I address such type of questions by using a combination of computational, molecular and cell biology methods. The two long-term goals of my research are to improve the molecular diagnosis of splicing mutations causing human genetic disease and to elucidate the role of alternative splicing events in their biological contexts. In the future I also hope to identify new therapeutic targets, and/or to develop RNA-based therapies for human diseases.|
- Development of Therapeutic Approaches to Overcome Drug Resistance Conferred by a Novel Bim Deletion Polymorphism in Chronic Myelogenous Leukemia and EGRF-Mutated Non-Small-Cell Lung Cancer
- Implications of Splicing Mechanisms in Genetic Diseases and the Immune System Via CD46
- Mechanisms of Splicing and their Implication in Human Genetic Disease
- Kubota T, Roca X, Kimura T, Kokunai Y, Nishino I, Sakoda S, Krainer AR, and Takahashi MP. (2011). A mutation in a rare type of intron in a sodium-channel gene results in aberrant splicing and causes myotonia. Human Mutation, 32, 1-10.
- Bernard Cher TH, Chan HS, Klein GF, Jabkowski J, Schadenböck-Kranzl G, Zach O, Roca X, Law SK. (2011). A novel 3' splice-site mutation and a novel gross deletion in leukocyte adhesion deficiency (LAD)-1. Biochemical and Biophysical Research Communications, 404(4), 1099-1104.
- Roca X, Krainer AR. (2009). A splicing component adapted to gene silencing.. Nature Biotechnology, 27(3), 250-251.
- Roca X, Krainer AR. (2009). Recognition of atypical 5' splice sites by shifted base-pairing to U1 snRNA. Nature Structural and Molecular Biology, 16(2), 176-182.
- Roca X, Olson AJ, Rao AR, Enerly E, Kristensen VN, Børresen-Dale AL, Andresen BS, Krainer AR, Sachidanandam R. (2008). Features of 5'-splice-site efficiency derived from disease-causing mutations and comparative genomics. Genome Research, 18(1), 77-87.