Biology subjects

Mazzocca, M.

Publications and source records attributed to Mazzocca, M..

6 recordsLinked to original sources

bioRxiv2026

SAF-A/HNRNPU regulates euchromatin dynamics and is required for nuclear envelope integrity

Defects in nuclear morphology are associated with cancer and premature ageing. Nuclear morphology is established by a balance of external forces produced by actin contractility and resistance provided by chromatin and the nuclear lamina. Euchromatin is decompacted to facilitate transcription, which has been shown to decrease local nucleosome motion. However, the role of transcription and euchromatic chromatin structure in nuclear envelope integrity are not clear. Here, we demonstrate that acute depletion of SAF- A/hnRNPU causes compaction of euchromatic regions and constriction of chromatin mobility, leading to loss of nuclear envelope integrity in a transcription-dependent manner. SAF-A is required in a dose-dependent manner to preserve nuclear shape under conditions of nuclear softening and elevated transcription. Our work identifies SAF-A as a dynamic scaffold that regulates chromatin structure and dynamics at sites of active transcription to preserve nuclear envelope mechanical tension.

cell biology↗

bioRxiv2026

NF-κB transcriptionally enhances p53 accumulation dynamics hampering DNA repair

Cells integrate multiple, often concurrent signals through intertwined genetic circuits whose dynamics shape transcriptional programs and cell fate decisions. Among these, the tumor suppressor p53 and the inflammatory transcription factor NF-{kappa}B are central regulators of stress responses in normal and cancer cells, yet their dynamic crosstalk under co-activation remains poorly characterized. Here, we combine genetic approaches, live cell imaging, transcriptomic analysis and mathematical modeling to dissect their dynamic interplay. We find that co-activation of NF-{kappa}B by the inflammatory cytokines TNF- and IL-1{beta} significantly enhance p53 nuclear accumulation upon genotoxic stress or Nutlin3a, and this effect is absent in NF-{kappa}B-deficient cells. Mechanistically, we show that cytokines induce an NF-{kappa}B-mediated increase of TP53 transcription, and mathematical modeling indicates that it is sufficient to account for the observed increased p53 accumulation. Functionally, NF-{kappa}B co-activation rewires p53-dependent transcriptional programs and impairs p53-mediated DNA repair following genotoxic stress, due to a shift of p53 dynamics from oscillatory to more sustained accumulation; p53 oscillatory dynamics and DNA repair remain largely unaltered in absence of NF-{kappa}B. Our results uncover an amplification of p53 response in presence of inflammatory cues that is transcriptionally mediated by NF-{kappa}B and that results, counterintuitively, in functional antagonism. SIGNIFICANCE STATEMENTp53 dynamics have been shown to correlate with the cellular responses of cancer cells to genotoxic insults such as those delivered by chemo- and radiotherapies. However, these dynamics have been mostly studied in settings that do not account for the pro-inflammatory cues that cancer cells might receive from the microenvironment. By addressing this gap, our study uncovers a previously unappreciated mechanism by which inflammatory signals induce an increased p53 accumulation, leading to reduced DNA repair capacity. Our results provide mechanistic understanding on the origin of p53-NF-{kappa}B antagonism and show how dynamically interconnected signalling pathways can produce counterintuitive functional outcomes. Translationally, the contribution of inflammation to the sensitivity of normal and cancer cells to DNA damage might be exploited in the management of chemo- and radiotherapies.

systems biology↗

bioRxiv2025

CD300LG is a receptor for triglyceride-rich lipoproteins that facilitates postprandial lipid clearance

Circulating triglycerides are principally transported by triglyceride-rich lipoprotein particles (TRLs) including very-low-density-lipoproteins (VLDL) and chylomicrons and require the activity of lipoprotein lipase for appropriate lipid processing and cellular uptake. Despite known genetic links between CD300LG variants and altered lipid profiles, the functional role of CD300LG in lipid metabolism remains unclear. In this study, we identify CD300LG as a crucial receptor for TRLs. Human genetic analyses reveal that reduced CD300LG protein levels are causally linked with CAD risk and increased number, diameter, and TAG concentration of TRLs. In mice, CD300LG deficiency results in postprandial hypertriglyceridemia independent of changes in VLDL secretion, intestinal lipid absorption, or lipoprotein lipase activity. Mechanistically, CD300LG acts as a receptor for TRLs through a direct interaction with ApoA4 to facilitate TRL clearance at the microvascular endothelium. These findings elucidate new functions for both CD300LG and ApoA4 and advance our general understanding of triglyceride metabolism.

physiology↗

bioRxiv2025

MYC modulates TOP2A diffusion to promote substrate detection and activity

Topoisomerases alleviate DNA supercoiling by cleaving and resealing DNA strands. Previously, we showed that the oncoprotein MYC recruits and stimulates topoisomerases to remove DNA entanglements generated by oncogenic transcription. Understanding this mechanism may suggest methods to inhibit MYC-driven topoisomerase activation, targeting tumor-specific transcription. Here, we demonstrate that the essential topoisomerase TOP2A in human cells exists in a dynamic equilibrium between sequestration in the nucleolus, substrate searching in transcription hubs, and active engagement on chromatin. This equilibrium is highly responsive to changes in DNA topology, allowing cells to regulate TOP2A levels. Using single molecule tracking, we show that MYC accelerates TOP2A diffusion in cells. We explain this phenotype by demonstrating that MYC limits TOP2A self-interaction in vitro, while decreasing the size of TOP2A complexes in cells. By increasing TOP2A diffusion, MYC promotes substrate binding and increases TOP2A engagement on chromatin genome-wide, revealing the mechanism underlying MYC stimulation of TOP2A activity.

cell biology↗

bioRxiv2025

Chromatin Dynamics are Highly Subdiffusive Across Seven Orders of Magnitude

Chromatin dynamics control the timescales of essential biological processes including DNA damage repair and activation of gene promoters by distal enhancers. Prior chromatin dynamics studies have reported widely varying degrees of subdiffusion, likely due to technical limitations. Here, we integrate MINFLUX--a recently developed single particle tracking method capable of achieving microsecond time resolution--with traditional tracking methodologies. We tracked chromatin dynamics across seven orders of magnitude in time in both human and mouse cells and found strongly subdiffusive dynamics ( [~] 0.3). These dynamics are only mildly sensitive to perturbations of transcription, histone acetylation, and topoisomerase II, while loop extrusion has a constraining effect. Search times under these observed dynamics are extremely short for nearby loci (<100 nm), but almost impossibly long over larger distances (>1 {micro}m). These findings have important implications for processes involving two locus contacts such as enhancer-promoter search and double-strand break repair.

biophysics↗

bioRxiv2022

Chromatin organization drives the exploration strategy of nuclear factors

Nuclear Factors (NFs) rapidly scan the genome for their targets, but the role of nuclear organization in such search is uncharted. Here we analyzed how multiple NFs explore chromatin, by combining live-cell single-molecule tracking with multifocal structured illumination of DNA density. We find that NFs displaying higher bound fractions sample DNA dense regions more exhaustively. Focusing on the tumor-suppressor p53, we demonstrated that this NF search for its targets by alternating between rapid diffusion in the interchromatin compartment and compact sampling of chromatin dense regions. Efficient p53 targeting requires balanced IDR/chromatin interactions: adding an exogenous IDR potentiates p53-mediated target gene activation, but excessive IDR/IDR interactions lead to p53 condensates, derailing its search and downregulating transcription. Our findings highlight the role of NF IDRs on their search and showcase a powerful method to generate traffic maps of the eukaryotic nucleus and dissect how nuclear organization guides NFs action.

biophysics↗