Biology subjects

Leyrer, J.

Publications and source records attributed to Leyrer, J..

3 recordsLinked to original sources

bioRxiv2026

Chromatin adaptors and TOPBP1 condensates cooperate to organize ATM signaling

DNA damage response proteins frequently accumulate in biomolecular condensates, yet how these structures cooperate with classical adaptor-mediated recruitment mechanisms to organize DNA damage signaling remains poorly understood. Here, we identify Treacle and the ATM adaptor NBS1 as prominent components of TOPBP1 condensates and show that these structures activate ATM signaling in the absence of DNA damage. At rDNA breaks, Treacle recruits NBS1 and TOPBP1 through genetically separable interaction modules. Acute protein degradation further revealed that Treacle is required for condensate assembly, whereas TOPBP1 remains continuously required for condensate maintenance. Finally, we show that efficient ATM accumulation at IR-induced DNA double-strand breaks similarly depends on both NBS1 and TOPBP1, indicating that this two-component mechanism is not restricted to nucleolar DNA damage. Together, our findings support a two-component model in which adaptor proteins provide molecular specificity, whereas TOPBP1 condensates create the spatial organization required for robust ATM signaling.

cell biology↗

bioRxiv2025

Treacle and MDC1 coordinate rDNA break repair by homologous recombination

The repair of DNA double-strand breaks in repetitive sequences is challenging because the abundance of potential templates for homology-directed repair (HDR) increases the risk of ectopic recombination and chromosome rearrangements. Relocalization of repair sites in repetitive sequences to a safe location prior to RAD51 loading has been observed in various organisms and is thought to limit aberrant recombination events. Here, we characterize this process in ribosomal DNA (rDNA) repeats, which reside within the nucleoli, specialized nuclear compartments dedicated to ribosome biogenesis. Induction of DSBs in rDNA triggers large-scale mobilization of damaged repeats from the nucleolar interior to the nucleolar periphery, where repair occurs. We show that this process is coordinated by the adaptor proteins Treacle and MDC1, which act sequentially to control nucleolar reorganization and repair factor recruitment. Treacle promotes rDNA mobilization through its role in nucleolar DNA damage signalling, whereas MDC1 acts downstream of nucleolar segregation to facilitate the recruitment of HDR factors at nucleolar caps. Following establishment of a {gamma}H2AX chromatin domain, MDC1-dependent RNF8-mediated chromatin ubiquitylation promotes BRCA1 recruitment via both the RNF168-dependent pathway and the RAP80-ABRAXAS complex. This in turn enables the sequential accumulation of PALB2 and RAD51 at nucleolar caps. Together, our findings demonstrate that RAD51 loading at rDNA breaks is tightly coupled to nucleolar reorganization and is mediated by dual RNF8-dependent signalling pathways, thereby ensuring that HDR is spatially restricted to the nucleolar periphery and reducing the risk of ectopic recombination between repetitive sequences.

cell biology↗

bioRxiv2022

Quantitative imaging reveals PI3Kδ inhibition reduces rhinovirus-induced damage of small airway epithelia in ex vivo cultured human precision cut lung slices from COPD patients

Chronic obstructive pulmonary disease (COPD) is one of the major causes of disability and death worldwide and a significant risk factor for respiratory infections. Rhinoviral infections are the most common trigger of COPD exacerbations which lead to a worsening of disease symptoms, decline in lung function and increased mortality. The lack of suitable disease models to study the relevant cellular and molecular mechanism hinders the discovery of novel medicines that prevent disease progression in exacerbating COPD patients. We used quantitative multi-color imaging of COPD and control patient derived human precision-cut lung slices (hPCLS) to study the impact of rhinovirus infection on the structure and function of the small airway epithelium. Data analysis highlighted that COPD-derived hPCLS have a higher cellular density and basal cell hyperplasia, more unciliated airway surface areas with mucus overproduction, and shorter cilia length compared to control hPCLS. In response to rhinovirus 16 infection, COPD-derived hPCLS secreted higher amounts of pro-inflammatory cytokines and displayed decreased epithelial integrity and reduced airway ciliation. Finally, treatment with a selective PI3K{delta} inhibitor reduced secretion of rhinovirus-induced cytokines and ameliorated rhinovirus-induced damage to COPD small airway epithelia. Thus, these data demonstrate the potential of quantitative imaging to assess complex airway functions in a patient-derived lung tissue model system, and indicate that targeting PI3K{delta} might be a promising therapeutic opportunity to limit rhinovirus-induced airway damage in exacerbating COPD patients. SummaryPI3K{delta} inhibition reduces rhinovirus-mediated damage of small airway epithelia from chronic obstructive pulmonary disease (COPD) patients

pathology↗