Biology subjects

Brunet, M.

Publications and source records attributed to Brunet, M..

6 recordsLinked to original sources

bioRxiv2023

The intrinsically disordered region of the E3 ubiquitin ligase TRIP12 induces the formation of chromatin condensates and interferes with DNA damage response.

Chromatin compaction is crucial for the faithful expression and integrity of the genome. Although largely studied, proteins and mechanisms that control the chromatin compaction are not entirely discovered. We previously showed that the nuclear HECT-type E3 ubiquitin ligase Thyroid hormone Receptor Interacting Protein 12 (TRIP12) is tightly associated to chromatin. As TRIP12 is overexpressed in several types of cancers, we explored herein the consequences of a TRIP12 overexpression on chromatin homeostasis. First, we established the TRIP12 proxisome and unveiled its pleiotropic role in chromatin regulation. Second, we demonstrated that TRIP12 overexpression leads to the formation of chromatin condensates enriched in heterochromatin marks via its intrinsically disordered region (IDR). We further discovered that the formation of TRIP12-mediated chromatin condensates is highly dynamic and driven by a mechanism of phase separation. Chromatin condensate formation depends on the TRIP12 concentration, the length of the TRIP12-IDR and relies on electrostatic interactions. We found that the formation of TRIP12 mediated-condensates alters cell cycle progression, genome accessibility, transcription as well as DNA damage response by inhibiting the accumulation of Mediator of DNA Damage Checkpoint 1 (MDC1). Altogether, this study reveals a novel dynamic role for TRIP12 in chromatin compaction independently of its ubiquitin ligase activity with important consequences on cellular homeostasis. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=155 SRC="FIGDIR/small/556486v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@13b3d90org.highwire.dtl.DTLVardef@46b991org.highwire.dtl.DTLVardef@1410bdeorg.highwire.dtl.DTLVardef@1722197_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2023

Alstrom syndrome proteins are novel regulators of centriolar cartwheel assembly and centrosome homeostasis in Drosophila

Centrioles play a central role in cell division by recruiting pericentriolar material (PCM) to form the centrosome. Alterations in centriole number or function lead to various diseases including cancer or microcephaly. Centriole duplication is a highly conserved mechanism in eukaryotes. Here, we show that the two Drosophila orthologs of the Alstrom syndrome protein 1 (Alms1a and Alms1b) are unexpected novel players of centriole duplication in fly. Using Ultrastructure Expansion Microscopy, we reveal that Alms1a is a PCM protein that is loaded proximally on centrioles at the onset of procentriole formation whereas Alms1b caps the base of mature centrioles. We demonstrate that chronic loss of Alms1 proteins affects PCM maturation, whereas their acute loss completely disrupts procentriole formation before Sas-6 cartwheel assembly. We establish that Alms1 proteins are required for the amplification of the Plk4-Ana2 pool at the duplication site and the subsequent Sas-6 recruitment. Thus, Alms1 proteins are novel critical but highly buffered regulators of PCM and cartwheel assembly in flies.

cell biology↗

bioRxiv2023

Seasonal dynamics of a glycan-degrading flavobacterial genus in a tidally-mixed coastal temperate habitat

Coastal marine habitats constitute hotspots of primary productivity. In temperate regions, this is due both to massive phytoplankton blooms and dense colonization by macroalgae that mostly store carbon as glycans, contributing substantially to local and global carbon sequestration. Because they control carbon and energy fluxes, algae-degrading microorganisms are crucial for coastal ecosystem functions. Environmental surveys revealed consistent seasonal dynamics of alga-associated bacterial assemblages, yet resolving what factors regulate the in situ abundance, growth rate and ecological functions of individual taxa remains a challenge. Here, we specifically investigated the seasonal dynamics of abundance and activity for a well-known alga-degrading marine flavobacterial genus in a tidally-mixed coastal habitat of the Western English Channel. We show that members of the genus Zobellia are a stable, low-abundance component of healthy macroalgal microbiota and can also colonize particles in the water column. This genus undergoes recurring seasonal variations with higher abundances in winter, significantly associated to biotic and abiotic variables. Zobellia can become a dominant part of bacterial communities on decaying macroalgae, showing a strong activity and high estimated in situ growth rates. These results provide insights into the seasonal dynamics and environmental constraints driving natural populations of alga-degrading bacteria that influence coastal carbon cycling. Originality-significance statementGlycan-degrading bacteria play a crucial role in marine habitats to remineralize organic carbon sequestered in algal biomass. Yet, resolving what factors regulate the in situ abundance, growth rate and ecological functions of individual taxa remains a challenge. Here, we investigate the seasonal dynamics of abundance and activity of an environmentally relevant glycan-degrading bacterial genus in two constrasted compartments of the same coastal habitat, i.e. the surface of diverse macroalgae and the water column. These results provide insights into the recurring temporal patterns and environmental constraints driving natural populations of alga-degrading bacteria that influence ocean carbon cycling.

microbiology↗

bioRxiv2023

The Loss of the E3 ubiquitin ligase TRIP12 inhibits Pancreatic Acinar Cell Plasticity and Tumor Cell Metastatic Capacity

Background & AimsAlthough specialized and dedicated to the production of digestive enzymes, pancreatic acinar cells harbor a high plasticity and are able to modify their identity. They undergo reversible acinar-to-ductal cell metaplasia (ADM) through epigenetic silencing of the acinar lineage gene program mainly controlled by PTF1a (Pancreas Transcription Factor 1a). ADM becomes irreversible in the presence of oncogenic Kras mutations and leads to the formation of preneoplastic lesions. We investigated the role of the E3 ubiquitin ligase Thyroid hormone Receptor Interacting Protein 12 (TRIP12), involved in PTF1a degradation, in pancreatic carcinogenesis. MethodsWe used genetically engineered mouse models of pancreas-selective Trip12 deletion, mutant Kras (G12D) and mutant Trp53 (R172H). We performed RNA sequencing analysis from acinar cells and cell lines derived from mice models tumors. We investigated the impact of TRIP12 deficiency on acute pancreatitis, tumor formation and metastasis development. ResultsTRIP12 is overexpressed in human pancreatic preneoplastic lesions and tumors. We show that a conditional deletion of TRIP12 in the pancreas during murine embryogenesis alters pancreas homeostasis and acinar cell genes expression patterns in adults. EGF induced-ADM is suppressed in TRIP12-depleted pancreatic acini. In vivo, a loss of TRIP12 prevents acini to develop ADM in response to pancreatic injury, the formation of Kras-induced pancreatic preneoplastic lesions, and impairs tumors and metastasis formation in the presence of mutated Trp53. TRIP12 is required for Claudin18.2 isoform expression in pancreatic tumors cells. ConclusionsOur study identifies TRIP12 as a novel regulator of acinar fate in the adult pancreas with an important dual role in pancreatic carcinogenesis, in initiation steps and in metastatic behavior of tumor cells. SynopsisThis study shows that Thyroid hormone Receptor Interacting Protein 12 plays an important dual role in the initiation steps and invasion of pancreatic carcinogenesis. Moreover, expression of TRIP12 switches on the expression of Claudin-18, a targetable biomarker of pancreatic tumors.

cancer biology↗

bioRxiv2022

MTALTND4, a second protein coded by nd4 impacts mitochondrial bioenergetics

Recent evidence suggests that the coding potential of the mitogenome is underestimated. We found a downstream alternative ATG initiation codon in the +3 reading frame of the human mitochondrial nd4 gene. This newly characterized alternative open reading frame (altORF) encodes a 99-amino acids long polypeptide, MTALTND4, which is conserved in primates. This small protein is localized in mitochondria and cytoplasm and is also found in the plasma, and it impacts mitochondrial physiology. Alternative mitochondrial peptides such as MTALTND4 may offer a new framework for the investigation of mitochondrial functions and diseases.

molecular biology↗

bioRxiv2021

Metabolic strategies of sharing pioneer bacteria mediating fresh macroalgae breakdown

Macroalgae represent huge amounts of biomass worldwide, largely recycled by marine heterotrophic bacteria. We investigated the strategies of "pioneer" bacteria within the flavobacterial genus Zobellia to initiate the degradation of fresh brown macroalgae, which has received little attention compared to the degradation of isolated polysaccharides. Zobellia galactanivorans DsijT could use macroalgae as a sole carbon source and extensively degrade algal tissues without requiring physical contact, via the secretion of extracellular enzymes. This indicated a sharing behaviour, whereby pioneers release public goods that can fuel other bacteria. Comparisons of eight Zobellia strains, and strong transcriptomic shifts in Z. galactanivorans cells using fresh macroalgae vs. isolated polysaccharides, revealed potential overlooked traits of pioneer bacteria. Besides brown algal polysaccharide degradation, they notably include stress resistance proteins, type IX secretion system proteins and novel uncharacterized Polysaccharide Utilization Loci. Overall, this work highlights the relevance of studying fresh macroalga degradation to fully understand the niche, metabolism and evolution of pioneer degraders, as well as their cooperative interactions within microbial communities, as key players in macroalgal biomass turnover.

microbiology↗