Biology subjects

Boissard, A.

Publications and source records attributed to Boissard, A..

6 recordsLinked to original sources

bioRxiv2026

Desmin p.R406W mutation is associated with arrhythmias through structural and electrophysiological remodeling

Background and AimsMutations in the desmin (DES) gene cause a variety of cardiomyopathies associated with arrhythmias, yet the electrophysiological consequences of these variants remain largely uncharacterized. The aim of this study was to investigate the pathogenic mechanisms of the de novo DES p.R406W variant, which was identified in a 9-year-old patient who suffered from severe ventricular arrhythmias and sudden cardiac death without overt structural heart disease. MethodsHuman induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying the DES p.R406W variant (including the patients line) were compared to isogenic controls. Action potentials (AP) of hiPSC-CMs were recorded using patch-clamp. Furthermore, 3D engineered heart tissues (EHTs) were generated from hiPSC-CMs and their APs were recorded with sharp microelectrodes. Analytical techniques also included transmission electron microscopy (TEM) and integrated transcriptomic and proteomic profiling. Finally, a heterozygous knock-in (KI) mouse model carrying the Des p.R405W ortholog was evaluated through surface ECG, echocardiography and ex vivo cardiac optical mapping. ResultsThe DES p.R406W mutation prolonged AP duration in IM-R406W hiPSC-CMs and EHTs vs Control ones. Multi-omics analysis of EHTs revealed a dysregulation of genes and proteins involved in contractile function, cell adhesion, and electrical activity. TEM imaging revealed changes in Z-disc architecture in mutant tissues. Twenty-week-old Des p.R405W KI mice exhibited ventricular conduction slowing (prolonged QRS) and a high susceptibility to ventricular tachyarrhythmias, likely due to reentrant mechanisms. Mild hypertrophy was also observed, but only in females. ConclusionThe DES p.R406W variant is highly pathogenic, causing electrical and structural remodeling of the myocardium. This study highlights the effectiveness of hiPSC-CMs and EHTs in recapitulating the clinical phenotype of desminopathy, providing a platform for investigating the mechanisms of early-onset cardiac arrhythmias and SCD.

pathology↗

bioRxiv2025

EGFR/TBK1-dependent mitochondrial quality control contributes to acquired resistance to temozolomide

Acquisition of secondary resistance to chemotherapy in cancer cells is an ill-characterized multi-step process. We conducted a non-supervised, global proteomic analysis of U251 glioma cells treated by temozolomide as they transit from drug-sensitive to tolerant and then resistant states. This unprecedented analysis revealed key mitochondrial evolutions throughout the process. Following an early stress substantiated by a transient peak of reactive oxygen species, mitochondrial quality control mechanisms enable emergence of the resistant population. We combined genome editing, targeted protein degradation via PROTAC, and pharmacologic inhibitors to investigate the mechanisms underlying stress resolution both at population and single cell scales (including microscopic evaluation and in-situ proximity ligation assays). These studies unravel a Src-activated EGFR and TBK1 axis that initiates autophagic recycling of mitochondria as a necessary step to the emergence of the resistant population.

cancer biology↗

bioRxiv2025

The Kinase CK1α coordinates Initiation and Termination of the cGAS-STING Pathway

The cGAS-STING pathway is an evolutionarily conserved antimicrobial defense mechanism that senses cytosolic DNA to trigger innate immune responses. cGAS and STING play dual roles in tumorigenesis, promoting antitumor immunity and cell death while fueling tumor growth and metastasis. However, the mechanisms fine-tuning this pathway remain elusive. Using proteomic approaches, we report that Casein Kinase 1 alpha (CK1) operates as a bimodal regulator of the cGAS-STING pathway. CK1 supports optimal DNA sensing by preventing the proteasomal degradation of cGAS driven by the cullin-RING ubiquitin ligase 3 (CRL3). Conversely, CK1 facilitates STING degradation and signaling termination in response to STING agonists, tempering IRF3 activation. Exploiting these counterposing functions, we show that selective degradation of CK1 with molecular-glue degraders impaired the survival of a triple-negative breast cancer cell line with chronic cGAS-STING activation and synergized with a STING agonist to kill acute myeloid leukemia cells. Thus, CK1s dual regulatory role in the cGAS-STING pathway presents a promising target for therapeutic development. TEASERThis study unveils CK1 as a bimodal regulator of the cGAS-STING pathway.

immunology↗

bioRxiv2023

The YARS Tyrosyl tRNA Synthetase Regulates Senescence Induction and Escape Through the Transcriptional Control of LIN9, a Member of the DREAM Complex

Senescence is a tumor suppressor mechanism triggered by oncogene expression and chemotherapy treatment. It orchestrates a definitive cessation of cell proliferation through the activation of the p53-p21 and p16-Rb pathways, coupled with the compaction of proliferative genes within heterochromatin regions. Some cancer cells have the ability to elude this proliferative arrest but the signaling pathways involved in circumventing senescence remain to be characterized. We have recently described that malignant cells capable of evading senescence have an increased expression of specific tRNAs, such as tRNA-Leu-CAA and tRNA-Tyr-GTA, alongside the activation of their corresponding tRNA ligases, namely LARS and YARS. We have previously shown that YARS promotes senescence escape by activating proliferation and cell cycle genes but its functions during this proliferative arrest remain largely unknown. In this study, we have continued to characterize the functions of YARS, describing non-canonical transcriptional functions of the ligase. Our results show that YARS is present in the nucleus of growing and senescent cells and interacts with the Trim28 transcriptional regulator. Importantly, YARS binds to the LIN9 promoter, a critical member of the Dream complex responsible for regulating cell cycle transcription. YARS facilitates the binding and the phosphorylation of the type II RNA polymerase and promotes the deposit of activating epigenetic marks on the LIN9 promoter. Consequently, during senescence escape, YARS promotes LIN9 expression and both proteins are necessary to induce the proliferation of emergent cells. These results underscore the unconventional transcriptional functions of YARS in promoting senescence escape by activating LIN9 and likely influencing the functions of the Dream complex.

cancer biology↗

bioRxiv2020

tRNA Biogenesis and Specific Aminoacyl-tRNA Synthetases Regulate Senescence Stability Under the Control of mTOR

Oncogenes or chemotherapy treatments trigger the induction of suppressive pathways such as apoptosis or senescence. Senescence was initially defined as a definitive arrest of cell proliferation but recent results have shown that this mechanism is also associated with cancer progression and chemotherapy resistance. Senescence is therefore much more heterogeneous than initially thought. How this response varies is not really understood, it has been proposed that its outcome relies on the secretome of senescent cells and on the maintenance of their epigenetic marks. Using experimental models of senescence escape, we now described that the stability of this suppression relies on specific tRNAs and aminoacyl-tRNA synthetases. Following chemotherapy treatment, the DNA binding of the type III RNA polymerase was reduced to prevent tRNA transcription and induce a complete cell cycle arrest. By contrast, during senescence escape, specific tRNAs such as tRNA-Leu-CAA and tRNA-Tyr-GTA were up-regulated. Reducing tRNA transcription appears necessary to control the strength of senescence since RNA pol III inhibition through BRF1 depletion maintained senescence and blocked cell persistence. mTOR inhibition also prevented CIS escape in association with a reduction of tRNA-Leu-CAA and tRNA-Tyr-GTA expression. Further confirming the role of the tRNA-Leu-CAA and tRNA-Tyr-GTA, their corresponding tRNA ligases, YARS and LARS, were necessary for senescence escape. This effect was specific since the CARS ligase had no effect on persistence. YARS and LARS inactivation reduced cell emergence and proteomic analysis indicated that this effect was associated with the down-regulation of E2F1 target genes. Overall, these findings highlight a new regulation of tRNA biology during senescence and suggest that specific tRNAs and ligases contribute to the strength and heterogeneity of this suppression.

cancer biology↗

bioRxiv2018

Genomic prediction offers the most effective marker assisted breeding approach for ability to prevent arsenic accumulation in rice grains

The high concentration of arsenic in the paddy fields and, consequently, in the rice grains is a critical issue in many rice-growing areas. Breeding arsenic tolerant rice varieties that prevent As uptake and its accumulation in the grains is a major mitigation options. However, the genetic control of the trait is complex, involving large number of gene of limited individual effect, and raises the question of the most efficient breeding method. Using data from three years of experiment in a naturally arsenic-reach field, we analysed the performances of the two major breeding methods: conventional, quantitative trait loci based, selection targeting loci involved in arsenic tolerance, and the emerging, genomic selection, predicting genetic values without prior hypotheses on causal relationships between markers and target traits. We showed that once calibrated in a reference population the accuracy of genomic prediction of arsenic content in the grains of the breeding population was rather high, ensuring genetic gains per time unite close to phenotypic selection. Conversely, selection targeting quantitative loci proved to be less robust as, though in agreement with the literature on the genetic bases of arsenic tolerance, few target loci identified in the reference population could be validated in the breeding population.

genetics↗