Biology subjects

Ribas de Pouplana, L.

Publications and source records attributed to Ribas de Pouplana, L..

4 recordsLinked to original sources

bioRxiv2025

Characterization of Somatic Mutations in Human tRNA Genes Reveals Tumor-Specific Mutational Loads, and the Generation of tRNA Variants that Alter the Genetic Code

Transfer RNA genes (tDNAs) are essential genomic elements that safeguard translational fidelity. Using the T2T version of the human genome we have mapped the position of human tDNAs and analyzed their individual transcriptional activities. Then we have characterized, at single base resolution, the impact of somatic mutations in human tDNAs and its relationship to the transcriptional status of each gene. We confirm that tDNAs are hotspots for somatic mutagenesis, and show that they display mutational loads that are directly proportional to their transcription rates. Highly transcribed tDNAs in tumors or healthy tissues accumulate mutations at rates up to nine-fold higher than highly transcribed protein-coding genes. Mutational loads at tDNAs are tumor-specific, and increase with patient age. Mutations at structurally conserved tRNA positions appear to be under negative selection. Strikingly, anticodon nucleotides crucial for decoding frequently acquire somatic mutations, readily generating chimeric tRNAs species capable of systematically introducing amino acid substitutions across the proteome. Our results reveal a previously unrecognized source of somatic heterogeneity in human cancer and aging tissues that may directly impact upon translation efficiency and fidelity, and cause cell-specific proteostasis degeneration.

genomics↗

bioRxiv2024

Metabolic imprint of an intracellular pathogen drives histone hypermethylation and tunes the host transcriptional response to infection

Chlamydia trachomatis, an intracellular bacterium, highjacks metabolites from the host cell for its own proliferation. We provide evidence of global hypermethylation of the host proteome, including histones, during the late stages of infection. Single cell analyses revealed co-occurrence of several methylated residues on histones. Histone hypermethylation correlated with bacterial load and was prevented by antibiotic treatment. Mapping of trimethylation of histone 3 at residues K4 and K9 revealed a broad distribution throughout the chromatin. Nuclear fractions of infected cells exhibited a four-fold decrease of demethylase activity towards H3K4me3 and a two-fold increase in succinate concentration, a competitive inhibitor for the demethylase co-factor -ketoglutarate. Supplementation of the culture medium with dimethyl-ketoglutarate (DMKG) or with iron, a second co-factor of histone lysine demethylases, reduced histone hypermethylation. DMKG supplementation modified the transcription of about one third of the infection-responsive genes, indicating that histone hypermethylation contributes to modulating the transcriptional response of the host to infection. Finally, chemical inhibition of histone demethylases in a mouse model of infection showed a moderate benefit regarding the outcome of infection. Overall, our data show that the metabolic pressure exerted by a pathogen with an intracellular lifestyle drives epigenetic changes in infected cells.

cell biology↗

bioRxiv2023

Common evolutionary origins of the bacterial glycyl tRNA synthetaseand alanyl tRNA synthetase

Aminoacyl-tRNA synthetases (aaRSs) establish the genetic code. Each aaRS covalently links a given canonical amino acid to a cognate set of tRNA isoacceptors. Glycyl tRNA aminoacylation is unusual in that it is catalyzed by different aaRSs in different lineages of the Tree of Life. We have investigated the phylogenetic distribution and evolutionary history of bacterial glycyl tRNA synthetase (bacGlyRS). This enzyme is found in early diverging bacterial phyla such as Firmicutes, Acidobacteria, and Proteobacteria, but not in archaea or eukarya. We observe relationships between each of six domains of bacGlyRS and six domains of four different RNA-modifying proteins. Component domains of bacGlyRS show common ancestry with i) the catalytic domain of class II tRNA synthetases; ii) the HD domain of the bacterial RNase Y; iii) the body and tail domains of the archaeal CCA-adding enzyme; iv) the anti-codon binding domain of the arginyl tRNA synthetase; and v) a previously unrecognized domain that we call ATL (Ancient tRNA latch). The ATL domain is found only in bacGlyRS and in the universal alanyl tRNA synthetase (uniAlaRS). Further, the catalytic domain of bacGlyRS is more closely related to the catalytic domain of uniAlaRS than to any other aminoacyl tRNA synthetase. The combined data suggest that the ATL and catalytic domains of these two enzymes are ancestral to bacGlyRS and uniAlaRS, which emerged from common protein ancestors by bricolage, stepwise accumulation of protein domains, before the last universal common ancestor of life.

evolutionary biology↗

bioRxiv2020

Subcellular relocalization and nuclear redistribution of the RNA methyltransferases TRMT1 and TRMT1L upon neuronal activation

RNA modifications are dynamic chemical entities that regulate RNA fate, and an avenue for environmental response in neuronal function. However, which RNA modifications may be playing a role in neuronal plasticity and environmental responses is largely unknown. Here we characterize the biochemical function and cellular dynamics of two human RNA methyltransferases previously associated with neurological dysfunction, TRMT1 and its homolog, TRMT1-like (TRMT1L). Using a combination of next-generation sequencing, LC-MS/MS, patient-derived cell lines and knockout mouse models, we confirm the previously reported dimethylguanosine (m 2,2 G) activity of TRMT1 in tRNAs, as well as reveal that TRMT1L, whose activity was unknown, is responsible for methylating a subset of cytosolic tRNA Ala (AGC) isoacceptors at position 26. Using a cellular in vitro model that mimics neuronal activation and long term potentiation, we find that both TRMT1 and TRMT1L change their subcellular localization upon neuronal activation. Specifically, we observe a major subcellular relocalization from mitochondria and other cytoplasmic domains (TRMT1) and nucleoli (TRMT1L) to different small punctate compartments in the nucleus, which are as yet uncharacterized. This phenomenon does not occur upon heat shock, suggesting that the relocalization of TRMT1 and TRMT1L is not a general reaction to stress, but rather a specific response to neuronal activation. Our results suggest that subcellular relocalization of RNA modification enzymes play a role in neuronal plasticity and transmission of information, presumably by addressing new targets.

molecular biology↗