Translational Control and Metabolism

Junior Research Group Translational Control and Metabolism

Dr. Fabricio Loayza-Puch

Scheme of the differential ribosome codon reading (diricore) approach
© dkfz.de

The demand for building blocks in cancer cells differs greatly from the one of a normal cell. In order to divide, a cell must duplicate its protein content, a process that requires large amounts of energy and amino acid resources. To cope with a higher demand of energy and building blocks, cancer cells rewire profoundly their metabolic networks. However, the metabolic changes a tumor undergoes to adapt to deregulated growth might expose vulnerabilities that can be exploited for therapy. To exploit amino acid vulnerabilities for cancer therapy, one must first identify which amino acid is the most restrictive to the tumor. Our laboratory uses a combination of innovative genomics tools, molecular biology, animal models, and bioinformatics to uncover these metabolic limitations in cancer. Recently, we developed a novel approach to detect restrictive amino acids in cells and tumors. The rationale of our approach is based on differential ribosome codon reading (diricore); we make use of ribosome profiling to detect ribosomes stalled at specific codons. The accumulation of ribosomes at a particular codon indicates that the corresponding aminoacylated tRNA might be limiting and suggests a deficiency of the amino acid. The diricore approach can be used as a platform to sense these amino acid deficiencies in cells and tumors and to expose the weaknesses of tumor's metabolic remodeling.

Future Outlook
RNA functions not only as a carrier of genetic information, but also as a catalyst and guide for the processing or regulation of other RNA molecules. Using a combination of innovative sequencing techniques and functional genomics, our group aims to understand the role of mRNA translation in cancer and metastasis. We explore the global impact of RNA modifications and the role of non-coding RNAs on mRNA translation. At the same time, we use the global positional information of ribosomes as a readout to infer metabolic deficiencies in tumors, such limitations have the potential to be exploited as novel cancer therapies.

Contact

Dr. Fabricio Loayza-Puch
Translational Control and Metabolism (B250)
Deutsches Krebsforschungszentrum
Im Neuenheimer Feld 280
69120 Heidelberg
Tel: +49 6221 42 3632

Selected Publications

  • Slobodin B, Han R, Calderone V, Oude Vrielink J, Loayza-Puch F, Elkon R, Agami R. (2017). Transcription Impacts the Efficiency of mRNA Translation via Co-transcriptional N6-adenosine Methylation. Cell, 169(2):326-337
  • Loayza-Puch F*, Rooijers K*, Buil L, Zijlstra J, Oude Vrielink JAF, Lopes R, Ugalde AP, van Breugel P, Bex A, Hofland I, Wesseling I, van Tellingen O, Agami R (2016). Tumour-specific proline vulnerability uncovered by differential ribosome codon reading. Nature, 25;530 (7591): 490-494
  • Rooijers K*, Loayza-Puch F*, Nijtmans L, Agami R (2013). Ribosome profiling reveals features of normal and disease-associated mitochondrial translation.. Nature Communications 2:2886
  • Jenal M*, Elkon R*, Loayza-Puch F*, van Haaften G, Kuhn U, Menzies FM, Vrielink JA, Bos AJ, Drost J, Rooijers K et al (2012). The poly(a)-binding protein nuclear 1 suppresses alternative cleavage and polyadenylation sites. Cell, 149(3):538-553
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