Marta Rodríguez-Escribà

University of California, San Francisco

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Noelia Camacho

Institute for Research in Biomedicine

Lluı́s Ribas de Pouplana

Institute for Research in Biomedicine

Aleksandar Rajkovic

University of California, San Francisco

Svetlana A. Yatsenko

Stanford University

Eva Maria Novoa

Centre for Genomic Regulation

Adrian Gabriel Torres

Institute for Research in Biomedicine

Philip A. Knobel

University Hospital of Zurich

Daria Picchioni

Institute for Research in Biomedicine

Albert Antolin-Fontes

Institute for Research in Biomedicine

Stacy L. Hovde

Michigan State University

Cooperative Institutions

Institute for Research in Biomedicine

Institució Catalana de Recerca i Estudis Avançats

Barcelona Institute for Science and Technology

University of California, San Francisco

University of Pittsburgh

Inserm

University of Pittsburgh Medical Center

Institute of Science and Technology

Centro de Investigación Biomédica en Red

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Heterozygous TP63 pathogenic variants in isolated primary ovarian insufficiency

Journal of Assisted Reproduction and Genetics (2023)

Rachel Vanderschelden Marta Rodríguez-Escribà Serena H. Chan Andrea J. Berman Aleksandar Rajkovic

Sanger sequencing

Human genetics

Exome

10.1007/s10815-023-02886-w

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Citations (2)

STRUCTURAL VARIANTS IN GENOMES OF PATIENTS WITH RECURRENT PREGNANCY LOSS (RPL): THE UTILITY OF OPTICAL GENOME MAPPING (OGM)

Fertility and Sterility (2024)

Roy G. Handelsman Kajal Verma Marta Rodríguez-Escribà Christina G. Tise Hakan Çakmak

10.1016/j.fertnstert.2024.07.624

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Citations (0)

Inosine modifications in human tRNAs are incorporated at the precursor tRNA level

Nucleic Acids Research (2015)

Adrian Gabriel Torres David Piñeyro Marta Rodríguez-Escribà Noelia Camacho Oscar Reina

Transfer RNAs (tRNAs) are key adaptor molecules of the genetic code that are heavily modified post-transcriptionally. Inosine at the first residue of the anticodon (position 34; I34) is an essential widespread tRNA modification that has been poorly studied thus far. The modification in eukaryotes results from a deamination reaction of adenine that is catalyzed by the heterodimeric enzyme adenosine deaminase acting on tRNA (hetADAT), composed of two subunits: ADAT2 and ADAT3. Using high-throughput small RNA sequencing (RNAseq), we show that this modification is incorporated to human tRNAs at the precursor tRNA level and during maturation. We also functionally validated the human genes encoding for hetADAT and show that the subunits of this enzyme co-localize in nucleus in an ADAT2-dependent manner. Finally, by knocking down HsADAT2, we demonstrate that variations in the cellular levels of hetADAT will result in changes in the levels of I34 modification in all its potential substrates. Altogether, we present RNAseq as a powerful tool to study post-transcriptional tRNA modifications at the precursor tRNA level and give the first insights on the biology of I34 tRNA modification in metazoans.

Inosine

Deamination

Genetic Code

10.1093/nar/gkv277

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Citations (99)

Human tRNAs with inosine 34 are essential to efficiently translate eukarya-specific low-complexity proteins

Nucleic Acids Research (2021)

Adrian Gabriel Torres Marta Rodríguez-Escribà Marina Marcet‐Houben Helaine Graziele Santos Vieira Noelia Camacho

The modification of adenosine to inosine at the wobble position (I34) of tRNA anticodons is an abundant and essential feature of eukaryotic tRNAs. The expansion of inosine-containing tRNAs in eukaryotes followed the transformation of the homodimeric bacterial enzyme TadA, which generates I34 in tRNAArg and tRNALeu, into the heterodimeric eukaryotic enzyme ADAT, which modifies up to eight different tRNAs. The emergence of ADAT and its larger set of substrates, strongly influenced the tRNA composition and codon usage of eukaryotic genomes. However, the selective advantages that drove the expansion of I34-tRNAs remain unknown. Here we investigate the functional relevance of I34-tRNAs in human cells and show that a full complement of these tRNAs is necessary for the translation of low-complexity protein domains enriched in amino acids cognate for I34-tRNAs. The coding sequences for these domains require codons translated by I34-tRNAs, in detriment of synonymous codons that use other tRNAs. I34-tRNA-dependent low-complexity proteins are enriched in functional categories related to cell adhesion, and depletion in I34-tRNAs leads to cellular phenotypes consistent with these roles. We show that the distribution of these low-complexity proteins mirrors the distribution of I34-tRNAs in the phylogenetic tree.

Inosine

10.1093/nar/gkab461

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Citations (24)

Coordination of Mitochondrial Protein Synthesis and DNA Replication Through a Novel Aminoacyl-Trna Synthetase Architecture

SSRN Electronic Journal (2018)

Daria Picchioni Albert Antolin-Fontes Noelia Camacho Claus Schmitz Alba Pons-Pons

The aminoacylation of tRNAs by aminoacyl-tRNA synthetases (ARS) is a central reaction in biology. Multiple regulatory pathways utilize the aminoacylation status of cytosolic tRNAs to monitor and regulate metabolism. The existence of equivalent regulatory networks within the mitochondria is unknown. Here we describe a functional network that couples protein synthesis to DNA replication in animal mitochondria. We show that a duplication of the gene coding for mitochondrial seryl-tRNA synthetase (SerRS2) generated a paralog protein (SLIMP) in arthropods that forms a heterodimeric complex with a SerRS2 monomer. This seryl-tRNA synthetase variant is essential for protein synthesis and mitochondrial respiration. In addition, SLIMP interacts with the substrate binding domain of the mitochondrial protease LON, thus stimulating proteolysis of the DNA-binding protein TFAM, and repressing mitochondrial DNA (mtDNA) replication. Thus, mitochondrial translation is directly coupled to mtDNA replication by a network based upon a profound structural modification of an animal ARS.

Amino Acyl-tRNA Synthetases

10.2139/ssrn.3305578

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Sohlh1loss of function male and female infertility model impacts overall health beyond gonadal dysfunction in mice

Biology of Reproduction (2023)

Marta Rodríguez-Escribà Beatriz Rodríguez‐Alonso Shweta Belur Aleksandar Rajkovic

Abstract Reproductive longevity is associated with health outcomes. Early menopause, loss of ovarian function, and male infertility are linked to shorter lifespan and increased adverse health outcomes. Here we examined the extragonadal effects of whole animal loss of spermatogenesis and oogenesis specific basic helix–loop–helix 1 (Sohlh1) gene in mice, a well-described mouse model of female and male infertility. Sohlh1 encodes a transcription factor that is primarily expressed in the male and female germline and regulates germline differentiation. The Sohlh1 knockout mouse model, just like human individuals with SOHLH1 loss of function, presents with hypergonadotropic hypogonadism and loss of ovarian function in females and impaired spermatogenesis in males, with a seemingly gonad restricted phenotype in both sexes. However, extragonadal phenotyping revealed that Sohlh1 deficiency leads to abnormal immune profiles in the blood and ovarian tissues of female animals, sex-specific alterations of metabolites, and behavior and cognition changes. Altogether, these results show that Sohlh1 deficiency impacts overall health in both male and female mice.

Knockout mouse

10.1093/biolre/ioad008

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Citations (1)

Pathogenic Variants in ZSWIM7 Cause Primary Ovarian Insufficiency

The Journal of Clinical Endocrinology & Metabolism (2022)

Svetlana A. Yatsenko Fatih Gürbüz Ali Kemal Topaloğlu Andrea J. Berman Pierre‐Marie Martin

Primary ovarian insufficiency (POI) is a genetically heterogeneous condition associated with infertility and an increased risk of comorbidities. An increased number of genes implicated in DNA damage response pathways has been associated with POI as well as predisposition to cancers.

Candidate gene

Unexplained infertility

10.1210/clinem/dgac090

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Citations (9)

Detection of Inosine on Transfer RNAs without a Reverse Transcription Reaction

Biochemistry (2018)

Adrian Gabriel Torres Thomas F. Wulff Marta Rodríguez-Escribà Noelia Camacho Lluı́s Ribas de Pouplana

Inosine at the "wobble" position (I34) is one of the few essential posttranscriptional modifications in tRNAs (tRNAs). It results from the deamination of adenosine and occurs in bacteria on tRNAArgACG and in eukarya on six or seven additional tRNA substrates. Because inosine is structurally a guanosine analogue, reverse transcriptases recognize it as a guanosine. Most methods used to examine the presence of inosine rely on this phenomenon and detect the modified base as a change in the DNA sequence that results from the reverse transcription reaction. These methods, however, cannot always be applied to tRNAs because reverse transcription can be compromised by the presence of other posttranscriptional modifications. Here we present SL-ID (splinted ligation-based inosine detection), a reverse transcription-free method for detecting inosine based on an I34-dependent specific cleavage of tRNAs by endonuclease V, followed by a splinted ligation and polyacrylamide gel electrophoresis analysis. We show that the method can detect I34 on different tRNA substrates and can be applied to total RNA derived from different species, cell types, and tissues. Here we apply the method to solve previous controversies regarding the modification status of mammalian tRNAArgACG.

Inosine

Deamination

Transcription

10.1021/acs.biochem.8b00718

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Citations (15)

Mitochondrial Protein Synthesis and mtDNA Levels Coordinated through an Aminoacyl-tRNA Synthetase Subunit

Cell Reports (2019)

Daria Picchioni Albert Antolin-Fontes Noelia Camacho Claus Schmitz Alba Pons-Pons

The aminoacylation of tRNAs by aminoacyl-tRNA synthetases (ARSs) is a central reaction in biology. Multiple regulatory pathways use the aminoacylation status of cytosolic tRNAs to monitor and regulate metabolism. The existence of equivalent regulatory networks within the mitochondria is unknown. Here, we describe a functional network that couples protein synthesis to DNA replication in animal mitochondria. We show that a duplication of the gene coding for mitochondrial seryl-tRNA synthetase (SerRS2) generated in arthropods a paralog protein (SLIMP) that forms a heterodimeric complex with a SerRS2 monomer. This seryl-tRNA synthetase variant is essential for protein synthesis and mitochondrial respiration. In addition, SLIMP interacts with the substrate binding domain of the mitochondrial protease LON, thus stimulating proteolysis of the DNA-binding protein TFAM and preventing mitochondrial DNA (mtDNA) accumulation. Thus, mitochondrial translation is directly coupled to mtDNA levels by a network based upon a profound structural modification of an animal ARS.

Amino Acyl-tRNA Synthetases

Aminoacylation

TFAM

10.1016/j.celrep.2019.03.022

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Citations (20)