Biology subjects

Boumendil, C.

Publications and source records attributed to Boumendil, C..

4 recordsLinked to original sources

bioRxiv2025

Biomolecular condensates at the nuclear pore basket maintain global chromatin organization

Nuclear pore complexes are the only gateway between the nucleus and cytoplasm in eukaryotic cells during interphase. Specificity of transport is ensured by a size-dependent permeability barrier, which has so far been attributed to intrinsically disordered phenylalanine-glycine (FG) repeat- containing nucleoporins located in the central channel of the nuclear pores. We show that the coiled-coil domain of the main component of the nuclear pore basket, the non-FG protein TPR, encompasses intrinsically disordered regions. This "disordered coiled-coil domain" allows it to form biomolecular condensates in vivo, drives mechanical exclusion of heterochromatin, and defines a new permeability barrier at the nuclear basket. This work therefore highlights unconventional properties of coiled-coil domains at the nuclear pore basket and bridges the biophysics of such domains with nuclear architecture, chromatin spatial organization and nucleocytoplasmic transport.

cell biology↗

bioRxiv2024

TPR is required for cytoplasmic chromatin fragment formation during senescence

During oncogene-induced senescence there are striking changes in the structure of the nucleus and the organisation of heterochromatin. This is accompanied by activation of a pro-inflammatory gene expression programme - the senescence associated secretory phenotype (SASP) - driven by transcription factors such as NF-{kappa}B. Here we show that TPR, a protein of the nuclear pore complex basket, is required for the very early activation of NF-{kappa}B signalling during the stress-response phase of oncogene-induced senescence. This is prior to activation of the SASP and occurs without affecting NF-{kappa}B nuclear import. We show that TPR is required for the activation of TBK1 signalling at these early stages of senescence and we link this to the formation of heterochromatin-enriched cytoplasmic chromatin fragments thought to bleb off from the nuclear periphery. These cytoplasmic chromatin fragments appear to lack nuclear pore components. Our data suggest that TPR at the nuclear pore is involved in the loss of structural integrity of the nuclear periphery during senescence. We propose that this acts as a trigger for activation of cytoplasmic nucleic acid sensing, NF-{kappa}B signalling, and activation of the SASP, during senescence.

cell biology↗

bioRxiv2019

Cornelia-de-Lange syndrome-associated mutations cause a DNA damage signalling and repair defect

Cornelia de Lange Syndrome is a multisystem developmental disorder typically caused by mutations in the gene encoding the cohesin loader NIPBL. The associated phenotype is generally assumed to be the consequence of aberrant transcriptional regulation. Recently, we identified a residue substitution in BRD4 associated with a Cornelia de Lange-like syndrome, that reduces BRD4 binding to acetylated histones. Here we show that, although this mutation reduces BRD4-occupancy at enhancers in mouse embryonic stem cells, it does not affect transcription. Rather it delays the cell cycle, increases DNA damage signalling, and perturbs regulation of DNA repair in mutant cells. This uncovers a new role for BRD4 in DNA repair pathway choice. Furthermore, we find evidence of a similar increase in DNA damage signalling in cells derived from NIPBL-deficient individuals, suggesting that defective DNA damage signalling and repair is also a feature of typical Cornelia de Lange Syndrome.

cell biology↗

bioRxiv2018

Nuclear pore density controls heterochromatin reorganization during senescence

Oncogene induced senescence (OIS) is a cell cycle arrest program triggered by oncogenic signalling. An important characteristic of OIS is activation of the senescence associated secretory phenotype (SASP)1 which can reinforce cell cycle arrest, lead to paracrine senescence but also promote tumour progression2-4. Concomitant with cell cycle arrest and the SASP activation, OIS cells undergo a striking nuclear chromatin reorganization, with loss of heterochromatin from the nuclear periphery and the appearance of internal senescence-associated heterochromatin foci (SAHF)5. The mechanisms by which SAHF are formed, and their role in cell cycle arrest and expression of the SASP, remain poorly understood. Here we show that nuclear pore density increases during OIS and is responsible for SAHF formation. In particular, we show that the nucleoporin TPR is required for both SAHF formation and maintenance. The TPR-induced loss of SAHF does not affect cell cycle arrest but completely abrogates the SASP. Our results uncover a previously unknown role of nuclear pores in heterochromatin reorganization in mammalian nuclei and in senescence, which uncouples the cell cycle arrest from the SASP.

cell biology↗