Group Javier Martinez

Connecting RNA processing to metabolism, cellular homeostasis and disease

On this page

The Question

We are curious minds and therefore our interests evolve together with discoveries. Yet, the central topic persists: the processing of RNA molecules, and how defects may lead to disease. Within such a broad topic, we focus on “non-canonical RNA splicing”, driving splicing of pre-tRNAs and Xbp1 mRNA during the Unfolded Protein Response. We dissect these processes at the biochemical, cellular and structural levels. An overarching question is, which factors catalyze and regulate non-canonical RNA splicing? A central player is the tRNA ligase complex, which keeps surprising us with recent links to oxidative stress, dedicated isoforms in nucleus and cytoplasm, a particular degradation pathway, and a potential role in RNA export pathways. Through a privately funded project – dbaexperiment.org – and with a biochemical approach, we aim to reveal the molecular mechanism leading to Diamond Blackfan Anemia Syndrome (DBAS) caused by a missense mutation in RPS19.

The Approach

The Martinez Lab uses molecular biology, biochemistry and bioinformatics to identify key players in RNA metabolism and study their functions. This “in vitro” approach entails protein purification, co-evolution analysis, immunoprecipitation, mass spectrometry and tailored cell lines, and is boosted by “in vivo” and “in silico” structural biology. In vivo studies – mutating or deleting target genes – have been, and are being done through collaborations. In essence, the Lab embraces curiosity-driven, solid and well-controlled basic science, with a keen interest in links to disease and potential cures.

Javier Martinez

Javier Martinez obtained his PhD in Argentina, characterizing “cruzipain”, a major cysteine-proteinase in Trypanosoma cruzi. As a Post-Doc, he turned into RNA biology to identify the poly(A) ribonuclease PARN and the RNA-induced silencing complex – RISC – in human cells. As a Junior Group Leader at IMBA, Javier and his team discovered and characterized the RNA kinase CLP1 and the tRNA ligase complex, and these findings redirected his laboratory towards non-canonical RNA splicing, an essential pathway for the maturation of transfer RNAs. Javier is a Group Leader at the Max Perutz Labs and Professor of the Medical University of Vienna. Long time ago (!) – Javier used to be youth champion of table tennis in Argentina. He is also a football (River Plate, Barcelona and Manchester City) and a Formula 1 fan, but group meetings do not deal with these topics…

Download CV

Main Building
Room: 2.113

   +43 1 4277 61803

Spotlights

Ashwin and FAM98 paralogs define nuclear and cytoplasmic RNA ligase complexes for tRNA biogenesis.

We have identified the function of Ashwin, the smallest and least studied subunit of the tRNA ligase complex (tRNA-LC). Ashwin contains a dual nuclear localization signal that allows the tRNA-LC to reach the nucleus and support pre-tRNA splicing. Ashwin displays exquisite specificity towards isoforms of the tRNA-LC containing FAM98B, rather than FAM98A or FAM98C. We envision Ashwin to have evolved to provide the tRNA-LC with a dual localization: nuclear, to splice pre-tRNAs, and cytoplasmic, to splice the mRNA encoding the transcription factor XBP1, essential during UPR. In the picture, fluorescent DDX1 within the tRNA-LC reaches the nucleus in wild type (WT) cells but not in cells where the Ashwin gene has been deleted. Expressing WT Ashwin sends the tRNA-LC back to the nucleus, but a mutant version of Ashwin, unable to associate with the tRNA-LC (aa 56-69 deleted), fails to do so.

Does the tRNA ligase complex link mutations in PYROXD1 to severe myopathies in human patients?<

Besides the core proteins critical for the assembly of the tRNA-ligase complex, an “expanded” set of subunits sustain its functionality. The latest such identified protein is PYROXD1, a “private” guardian shielding RTCB and its sensitive metal ions from oxidative damage, thus preserving pre-tRNA splicing and UPR in (aerobic) animals. New findings give an unexpected twist to PYROXD1 story: its variants cause a rare myopathy in humans. Do pathogenic variants fail to sustain the tRNA-LC, and thus turn unconventional RNA splicing a new process of interest in muscle diseases? Which aspects of (multi-layered) PYROXD1 biochemistry are affected in these variants? Finally, can their understanding pave the way to therapeutic approaches?

DBAS caused by missense mutation R62W in RPS19: A true ribosomopathy?

Molecular mechanisms underpinning Diamond-Blackfan Anemia Syndrome (DBAS), a disease characterized by the absence of red blood cells, remain elusive. Because mutations causing DBAS mainly occur in ribosomal proteins, researchers define DBAS as a “ribosomopathy”. We are interested in a Viennese family harboring a R62W missense mutation in RPS19. Polysome analysis of PBMCs (Peripheral Blood Mononuclear Cells) reveals no differences between affected and non-affected members (A). In contrast, when RPS19 is depleted in HeLa cells via RNAi, we detect severely reduced levels of the 40S ribosomal subunits (B). Through the expression of FLAG-tagged RPS19 wild type and R62W mutant followed by FLAG affinity purification and mass spectrometry in HEK293 cells (C), we have identified proteins specifically binding to RPS19 R62W (D). Depleting a top candidate in erythroblasts impairs proliferation or differentiation (E). Please see www.dbaexperiment.org.

Surprise… ANGEL2 is a 2′,3′-cyclic phosphatase rather than a deadenylase!

We have discovered ANGEL2, the first 2’,3’-cyclic phosphatase in human cells and previously predicted to be a deadenylase. The enzymatic activity has been characterized and its structure revealed in collaboration with Martin Jinek, in Zurich. ANGEL2 modulates pre-tRNA splicing and the UPR by hydrolysing the 2’,3’-cyclic phosphate at the end of 5’ RNA intermediates. ANGEL2 has recently been revealed as a mitochondrial enzyme.

RTCB is the catalytic subunits of the tRNA ligase complex. Actually, much more than that!

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 until 2011, when we identified HSPC117/RTCB as the catalytic subunit of the tRNA ligase complex. To become active for ligation, the tRNA ligase complex 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.

    Team

    Igor Asanovic
    PostDoc
       +43 1 4277 61815
    Room: 2.512

    Sebastian Guzman Perez
    PhD Student
       +43 1 4277 61821
    Room: 2.512

    Petra-Franziska Kalman
    Lab Manager
       +43 1 4277 61831
    Room: 2.515

    Moritz Leitner
    PhD Student
       +43 1 4277 61816
    Room: 2.512

    Javier Martinez
    Group Leader
       +43 1 4277 61803
    Room: 2.113

    Muhammet Samet Özeren
    Master Student
       +436641300204
    Room: 2.512

    Stefan Weitzer
    PostDoc
       +43 1 4277 61815
    Room: 2.512

    Martin Windberger
    Trainee
       +43 1 4277 61831
    Room: 2.515

    Selected Publications

    The oxidoreductase PYROXD1 uses NAD(P) as an antioxidant to sustain tRNA ligase activity in pre-tRNA splicing and unfolded protein response.

    2021 Molecular cell;81(12):2520, 2532.e16, 2520-2532.e16.
    PMID:  33930333

    Asanović 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.

    2020 Science (New York, N.Y.);369(6503):524, 530, 524-530.
    PMID:  32732418

    Pinto Paola H, Kroupova Alena, Schleiffer Alexander, Mechtler Karl, Jinek Martin, Weitzer Stefan, Martinez Javier

    Mechanistic basis for PYROXD1-mediated protection of the human tRNA ligase complex against oxidative inactivation.

    2025 Nature structural & molecular biology
    PMID:  40069351

    Loeff Luuk, Kroupova Alena, Asanović Igor, Boneberg Franziska M, Pfleiderer Moritz M, Riermeier Luca, Leitner Alexander, Ferdigg Andrè, Ackle Fabian, Martinez Javier, Jinek Martin

    View all Publications of Group Martinez

    Collaborations & Funding

    Doc.funds program “RNA@CORE, Molecular Mechanisms in RNA Biology”

    Javier Martinez coordinates the doc.funds program “RNA@CORE, Molecular Mechanisms in RNA Biology” funded by FWF. Doc.funds projects are peer-reviewed, highly interactive research networks with a focus on the education of candidate PhD students, in parallel with the achievement of their Doctoral Thesis. July 2023 to June 2027.

    Cluster of Excellence “Excellent Brains”

    The Group Martinez participates in the Cluster of Excellence “Excellent Brains” funded by FWF. The actual project investigates the “Functional interplay between the tRNA ligase complex and the RNA 3’-phosphate cyclase RTCA in neuronal RNA processing”. January 2025 to December 2029.

    Principal Investigator Project

    “The role of Ashwin, a subunit of the human tRNA ligase complex, in pre-tRNA processing and (m)RNA export”. July 2024 to June 2027.

    Principal Investigator Project

    “Ousted by metals: why is the tRNA ligase complex the prime target of a novel protein degradation pathway in human cells?” February 2026 to January 2029.

    27
    Search on the site...

    office@maxperutzlabs.ac.at

    +43 1 4277 240 01


    Vienna BioCenter
    Dr.-Bohr-Gasse 9, 1030 Vienna