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Our focus is on non-canonical RNA splicing found in two essential mammalian pathways, pre-tRNA splicing and the Unfolded Protein Response (UPR), and the uncommon 2’,3’-cyclic phosphate ended RNAs intermediates found therein. Which factors catalyze and regulate this type of RNA splicing? We have already identified and characterized two main players, the tRNA ligase complex and Archease, and recently revealed unexpected regulatory sources in oxidative stress and a novel unique RNA 2’,3’-cyclic phosphatase. These findings pave the way to find yet elusive 2’,3’-cyclic phosphate-ended RNAs in currently unknown pathways. In essence, our goal is to decipher the interplay between novel RNA processing factors and uncommon RNA termini. Through a privately funded project, and together with Dr. Leo Kager at St Anna Kinderspital and Prof. Josef Penninger and the IMBA Stem Cell Facility, we are also investigating Diamond Blackfan Anemia (DBA), a ribosomopathy that impairs red blood cell production.
Our laboratory relies on Molecular Biology and Biochemistry – our main strengths – to identify and characterize key players in RNA metabolism and study their functions. This “in vitro” approach is boosted by structural biology, proteomics and metabolomics analyses. In tandem, we adventure “in vivo” to understand the role of specific RNA processing factors in pre-tRNA splicing and UPR, both in health and in disease. For this, we turn to animal models – mutating or deleting involved genes – and cells from patients. In essence, we carry out curiosity driven basic science with a particular interest in links to disease.
Javier Martinez obtained his PhD from the University of Buenos Aires, Argentina. As a Post-Doc, he turned to RNA biology to identify and characterize the poly(A) ribonuclease PARN and the RNA-induced silencing complex, RISC. As a Junior Group Leader at IMBA, Javier and his team discovered the RNA kinase CLP1 and the tRNA ligase complex, and these findings redirected his laboratory towards pre-tRNA splicing and a type of non-canonical mRNA splicing during the Unfolded Protein Response. Javier has recently joined The Perutz Laboratories as a Professor at the Medical University of Vienna. Javier plays table tennis and is a football (Barcelona and River Plate) and Formula 1 fan!
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.
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.
The mammalian tRNA ligase complex mediates splicing of XBP1 mRNA and controls antibody secretion in plasma cells.
Jurkin, Jennifer; Henkel, Theresa; Nielsen, Anne Færch; Minnich, Martina; Popow, Johannes; Kaufmann, Therese; Heindl, Katrin; Hoffmann, Thomas; Busslinger, Meinrad; 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
HSPC117 is the essential subunit of a human tRNA splicing ligase complex.
Popow, Johannes; Englert, Markus; Weitzer, Stefan; Schleiffer, Alexander; Mierzwa, Beata; Mechtler, Karl; Trowitzsch, Simon; Will, Cindy L; Lührmann, Reinhard; Söll, Dieter; Martinez, Javier
The Group Martinez participates in the special Doctoral Program "RNA Biology" reviewed and funded by the Austrian Research Fund FWF.
The Group Martinez participates in the Special Research Program (SFB) "RNA-Reg - RNA regulation of the transcriptome" 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.
"RNA 3'-Phosphate Cyclase RTCD1 in mammalian RNA metabolism"
"The splicing of transfer RNA molecules: From enzymatic complexes to structures, physiology, evolution and disease"
Jennifer Jurkin for her project: “The tRNA ligase complex in neurogenesis and maintenance of neuronal functions.”