Dr Juan Valcarcel
No more applications being accepted
Funded PhD Project (Students Worldwide)
About the Project
This project will use genomics, bioinformatics, molecular biology and biochemistry to study molecular mechanisms of alternative pre-mRNA splicing regulation and their implications in cell proliferation, apoptosis and cell reprogramming. Our collaborators (e.g. Ben Blencowe, Roderic Guigó, Manuel Irimia, Ben Lehner and Michael Sattler) include geneticists, developmental, computational and structural biologists, organic chemists and molecular oncologists.
Questions to be investigated in this project include: "What are the functional relationships between the components of such a complex machinery as the spliceosome if we interrogate every alternatively spliced exon?" "Can we unravel the splicing code by assessing the effects of every possible mutation in a regulated exon?" "How can core splicing factors regulate cell type-specific splicing?" "What is the functional impact of recurrent mutations in splicing factors found in cancer?" "Can we understand why small molecules targeting spliceosome components display anti-tumor effects? And can these molecules be improved to affect only a few splicing events of therapeutic interest?" "Can we understand the reasons for the special vulnerability of cancer cells to changes in the activity of the spliceosome?"
The student will take part in the design of the project and will enroll in the CRG International PhD program, which includes science/practical courses, complementary skills training, follow up through a thesis committee and active participation in the organization of seminars and symposia. Former PhD students of the group are now postdocs, e.g. at Harvard University, Massachusetts Institute of Technology and King’s College London, supported by EMBO and Marie Sklodowska-Curie postdoctoral fellowships.
Applicants must have obtained a University Degree and a Masters Degree in a field of life sciences within the European Higher Education System (minimum 300 ECTS) .
Applications must be submitted online. Candidates must register in order to use the online application system.
Should you have specific questions on the scientific project, please contact [Email Address Removed] before submitting your application.
Funding Notes
The selected PhD student will receive an annual work contract with a competitive salary and additional funding.
Extramural funding of the group includes grants from the European Research Council (Advanced and Proof of Concept), Spanish Ministry of Economy and Competitiveness and Catalonian Government.
References
- Bechara et al. RBM5, RBM6 and RBM10 differentially regulate NUMB alternative splicing to control cancer cell proliferation. Molecular Cell, 52: 720-733 (2013)
- Papasaikas, Tejedor et al. Functional splicing network reveals extensive regulatory potential of the core Spliceosomal machinery. Molecular Cell, 57: 7-22 (2015)
- Tejedor et al. Genome-wide identification of FAS/CD95 alternative splicing regulators reveals links with iron homeostasis. Molecular Cell, 57: 23-38 (2015)
Julien et al. The complete local genotype-phenotype landscape for the alternative splicing of a human exon. Nature Communications, 7: 11558 (2016)
- Mourao et al. Structural basis for the recognition of proline-rich motifs in spliceosomal SmN/B/B’ proteins by the RBM5 OCRE domain in alternative splicing regulation. eLife 5. pii: e14707 (2016)
- Makowski, Vigevani et al. Sudemycin K: a synthetic anti-tumor splicing inhibitor variant with improved activity and versatile chemistry. ACS Chemical Biology, 12: 163 - 173 (2017)
- Vigevani et al. Molecular basis of differential 3' splice site sensitivity to anti-tumor drugs targeting U2 snRNP. Nature Communications, 8: 2100 (2017)
- Horiuchi, Perez-Cerezales et al. Impaired spermatogenesis, muscle and erythrocyte function in U12 intron-splicing defective Zrsr1 mutant mice. Cell Reports, (2018)
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