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RNA processing is an umbrella-term for a large number of chemical reactions that turn precursor RNAs into mature, functional molecules. At the core of our Lab is “Non-canonical RNA splicing”, a catalytic mechanism that removes single introns and joins remaining exons, strikingly different to the mRNA-devoted spliceosome. After several years of hard work, a podium of favorite enzymes and pathways conforms the pillars of our research. Yet, with a blend of curiosity, expertise, networking and intuition, we keep digging into non-canonical RNA splicing and adventuring into new, unexpected directions.
Having identified several players of the enzymatic machinery executing non-canonical RNA splicing, we are currently focusing on regulatory and physiological aspects of it. We discovered that the tRNA ligase complex (tRNA-LC) – a pillar of our research – is modulated by redox-mechanisms, involving metals, the antioxidant thioredoxin and the essential oxidoreductase PYROXD1, which protects the tRNA-LC against oxidation. Our current research also shows that PYROXD1 plays a critical function in iron metabolism, well beyond RNA biology. We also discovered that RNA molecules ended in 2’,3’-cyclic phosphates, substrates of the tRNA-LC, are processed by the cyclic phosphatase ANGEL2, which is itself regulated by post-translational modifications. The full interactome of the tRNA-LC and the individual roles of its subunits are also at the core of our Lab. Finally, we are making great progress in dissecting the mechanistic defects underlying Diamond Blackfan Anemia, a rare syndrome intimately linked to defects in RNA processing and iron metabolism. Please visit https://dbaexperiment.org.
Defining important as well as addressable questions is essential. We investigate, discover, communicate… and ask new questions. This is the science game that students and postdocs would enjoy when joining our group.
Our Laboratory relies on Biochemistry and Molecular Biology to identify and characterize key players in RNA processing. We boost this “in vitro” approach with structural biology – so far through collaborations with outstanding colleagues – and the proteomics, metabolomics and next generation sequencing facilities at the Vienna BioCenter. In parallel, and when appropriate, we adventure “in vivo” to understand the role of specific RNA processing factors and ribosomal proteins in health and disease, turning into animal models – mutating or deleting involved genes – or cells from patients.
Javier Martinez obtained his PhD from the University of Buenos Aires, Argentina. As a Post-Doc at the University of Uppsala, Sweden, he turned to RNA biology and identified and characterize the poly(A) ribonuclease PARN. Later, at the Max Planck Institute in Göttingen and The Rockefeller University in New York, he devoted to RNA interference and purified the RNA-induced silencing complex, RISC. As a Junior Group Leader at IMBA, in Vienna, Javier and his team continued revealing features of RNAi and RISC. However, the discovery of the RNA 5’ kinase CLP1 and the tRNA ligase complex redirected his laboratory towards the enzymatic machineries that catalyze non-canonical RNA splicing, an essential event for the maturation of pre-tRNA molecules and the reshaping of the Xbp1-mRNA during the Unfolded Protein Response. Javier’s lab is currently exploring areas beyond RNA biology. Javier is a Professor of the Medical University of Vienna and his laboratory is located at the Max Perutz Labs, within the vibrant Vienna BioCenter. Javier used to play table tennis and is a football (River Plate, Barcelona and Manchester City) and Formula 1 fan!
We have recently discovered the first 2’,3’-cyclic phosphatase in human cells. The enzymatic activity has been characterized and its structure revealed in collaboration with Martin Jinek, in Zurich. The novel and unique cyclic phosphatase is able to modulate pre-tRNA splicing and the UPR by hydrolysing the 2’,3’-cyclic phosphate at the end of 5’ tRNA exons and Xbp1-mRNA exons.
How did enzymes from Earth’s ancient anaerobic history, such as the RNA ligase RTCB, adapt to modern, aerobic environments? We have revealed an unexpected solution: RTCB, the catalytic subunit of the tRNA ligase complex co-evolved with a dedicated oxidoreductase, PYROXD1, which is linked to severe myopathies in humans. Paradoxically, PYROXD1 uses the principal prooxidative cofactor of the cell, NAD(P)+, as the ‘‘private’’ antioxidative protector of RTCB.
We are investigating the molecular mechanisms of Diamond-Blackfan Anemia (DBA), a disease characterized by a lack of red blood cell production which occurs shortly after birth. How and why do mutations in ribosomal proteins lead to this specific loss of red blood cells? We have recruited a family with two children who were diagnosed with DBA where the father carries a dominant mutation for DBA but does not present with the disease. Using a variety of techniques, we have been probing the effects of this particular DBA mutation within cells, and have established ex vivo red blood cell differentiation assays to validate our findings. See www.dbaexperiment.org.
We have identified CLP1 as a human RNA-kinase that phosphorylates siRNAs and tRNA 3’ exon halves at the 5’ end during in vitro pre-tRNA splicing. CLP1 is associated to the tRNA splicing endonuclease (TSEN) complex and is also part of the mRNA 3’ end formation machinery, with a still enigmatic function. Mutations in CLP1 lead to neurological diseases.
The process of pre-tRNA splicing requires removal of a single intron by the TSEN complex and joining of the resulting exon halves. The tRNA ligase activity remained elusive for three decades. In 2011, we identified HSPC117/RTCB as the catalytic subunit of the tRNA ligase complex. To catalyse multiple ligation reactions, the ligase requires Archease – also identified in our laboratory – as a co-factor. In addition, the tRNA ligase complex is responsible for the ligation of Xbp1-mRNA exons during the Unfolded Protein Response.
The oxidoreductase PYROXD1 uses NAD(P) + as an antioxidant to sustain tRNA ligase activity in pre-tRNA splicing and unfolded protein response
Asanovic, Igor; Strandback, Emilia; Kroupova, Alena; Pasajlic, Djurdja; Meinhart, Anton; Tsung-Pin, Pai; Djokovic, Nemanja; Anrather, Dorothea; Schuetz, Thomas; Suskiewicz, Marcin Józef; Sillamaa, Sirelin; Köcher, Thomas; Beveridge, Rebecca; Nikolic, Katarina; Schleiffer, Alexander; Jinek, Martin; Hartl, Markus; Clausen, Tim; Penninger, Josef; Macheroux, Peter; Weitzer, Stefan; Martinez, Javier
ANGEL2 is a member of the CCR4 family of deadenylases with 2',3'-cyclic phosphatase activity.
Pinto, Paola H; Kroupova, Alena; Schleiffer, Alexander; Mechtler, Karl; Jinek, Martin; Weitzer, Stefan; Martinez, Javier
CLP1 links tRNA metabolism to progressive motor-neuron loss.
Hanada, Toshikatsu; Weitzer, Stefan; Mair, Barbara; Bernreuther, Christian; Wainger, Brian J; Ichida, Justin; Hanada, Reiko; Orthofer, Michael; Cronin, Shane J; Komnenovic, Vukoslav; Minis, Adi; Sato, Fuminori; Mimata, Hiromitsu; Yoshimura, Akihiko; Tamir, Ido; Rainer, Johannes; Kofler, Reinhard; Yaron, Avraham; Eggan, Kevin C; Woolf, Clifford J; Glatzel, Markus; Herbst, Ruth; Martinez, Javier; Penninger, Josef M
The Group Martinez participates in the Special Research Program (SFB) “RNA-DECO, Decorating RNA for a purpose”. funded by the Austrian Science Fund FWF. SFB's are peer-reviewed, highly interactive research networks, established to foster long-term, interdisciplinary co-operation of local research groups working on the frontiers of their thematic areas.
“The oxidoreductase PYROXD1 links human myopathies to taurine biosynthesis, UPR and the control of the cellular metallome”.
“Characterization of human ANGEL2, the first described RNA 2’,3’-cyclic phosphatase in eukaryotic cells”