Biology subjects

Biressi, S.

Publications and source records attributed to Biressi, S..

4 recordsLinked to original sources

bioRxiv2026

Centrosome architecture and m6A-dependent gating of p53 surveillanceafter whole-genome doubling

Whole-genome doubling (WGD) generates a tetraploid state that challenges cellular homeostasis and is strongly selected against in TP53-proficient contexts. Although centrosome amplification serves as a structural correlate of genome doubling, how centrosomal features engage and sustain p53 surveillance remains incompletely understood. Here, we develop a genetically encoded MDM2-based fluorescent reporter to monitor Caspase-2 pathway activation in living cells after WGD. Combining pharmacological profiling and genome-wide CRISPR screening, we uncover a multi-layered regulation of p53 responses. We identify PLK1-dependent centriole maturation and subdistal appendage integrity as architectural determinants of PIDDosome-dependent Caspase-2 activation, independent of distal appendage assembly. We show that upon WGD, Caspase-2-mediated cleavage of MDM2 reshapes the p53-MDM2 regulatory loop, enabling sustained p53 signaling. This sustained output depends on the catalytic activity of METTL3 and associated m6A writer proteins. Together, these findings demonstrate that centrosome architecture and epitranscriptomic regulation cooperate to shape p53 surveillance after genome doubling. HighlightsO_LIWhole-genome doubling creates a surveillance state sensed by centrosome cluster architecture. C_LIO_LICaspase-2 activation converts the p53-MDM2 loop from negative to positive feedback. C_LIO_LIm6A methylation establishes competence of the p53 module for sustained output. C_LIO_LIA genetically encoded biosensor enables functional dissection of this circuit. C_LI

cell biology↗

bioRxiv2024

CD90 identifies distinct fractions of muscle stem cells with different modalities of activation and quiescence maintenance

Stem cell transition from quiescence to activation is crucial to guarantee productive tissue regeneration. Here we show that CD90 diversifies quiescent muscle stem cells (MuSCs) in murine and human muscle into two subpopulations differing in the kinetics of activation, CD90+ve MuSCs exhibiting a faster exit quiescence and predominating the initial phases of regeneration compared to CD90-ve MuSCs. In the absence of injury, the CD90+ve fraction is primed toward activation through an active CD90-AMPK axis but is maintained in quiescence through signals from the extracellular matrix. Our studies show that Collagen VI, which is preferentially expressed by CD90+ve MuSCs, binds to the Calcitonin receptor and plays a role in this context. Moreover, while the number of CD90+ve and CD90-ve subpopulations is similar in healthy muscles, the CD90-ve fraction predominates in the muscles of murine models of Duchenne and Ullrich congenital muscular dystrophies. These findings provide novel insights into the mechanistic determinants of MuSCs functional heterogeneity and have implications for understanding the stimulation of repair in dystrophic muscle.

cell biology↗

bioRxiv2023

Parkin R274W mutation affects muscle physiology via the PARIS-PGC-1α pathway

Recessive mutations in the Parkin gene (PRKN) are the most common cause of young-onset inherited parkinsonism. Parkin is a multifunctional E3 ubiquitin ligase that plays a variety of roles in the cell including the degradation of proteins and the maintenance of mitochondrial homeostasis, integrity, and biogenesis via the PARIS-PGC-1 pathway. In 2001 the R275W mutation in the PRKN gene was identified in two unrelated families with a multigenerational history of postural tremor, dystonia and parkinsonism. Drosophila models of Parkin R275W showed selective and progressive degeneration of dopaminergic neuronal clusters, mitochondrial abnormalities, and prominent climbing defects. In the Prkn mouse orthologue, the amino acid R274 corresponds to human R275. Here we described a muscle phenotype in R274W +/+ mice and discovered that a defective Parkin-PARIS-PGC-1 pathway may impact mitochondrial biogenesis and, eventually, myoblast proliferation and differentiation.

animal behavior and cognition↗

bioRxiv2020

PHARMACOLOGICAL PROTEIN INACTIVATION BY TARGETING FOLDING INTERMEDIATES

Recent computational advancements in the simulation of biochemical processes allow investigating the mechanisms involved in protein regulation with realistic physics-based models, at an atomistic level of resolution. Using these techniques to study the negative regulation of the androgen receptor (AR), we discovered a key functional role played by non-native metastable states appearing along the folding pathway of this protein. This unexpected observation inspired us to design a completely novel drug discovery approach, named Pharmacological Protein Inactivation by Folding Intermediate Targeting (PPI-FIT), based on the rationale of negatively regulating protein expression by targeting folding intermediates. Here, PPI-FIT was tested for the first time on the cellular prion protein (PrP), a cell surface glycoprotein playing a key role in fatal and transmissible neurodegenerative pathologies known as prion diseases. We predicted the all-atom structure of an intermediate appearing along the folding pathway of PrP, and identified four different small molecule ligands for this conformer, all capable of selectively lowering the expression of the protein by promoting its degradation. Our data support the notion that the level of target proteins could be modulated by acting on their folding pathways, implying a previously unappreciated role for folding intermediates in the biological regulation of protein expression.

biochemistry↗