Biology subjects

Meaburn, K.

Publications and source records attributed to Meaburn, K..

4 recordsLinked to original sources

bioRxiv2026

DNA damage at Lamina-Associated Domains triggers nuclear envelope reorganization and chromatin detachment to prevent nuclear envelope blebbing and genome instability.

The nuclear periphery anchors large, transcriptionally silent chromatin domains to the nuclear envelope and plays a central role in maintaining genome stability, acting as a dynamic hub for DNA repair. Nevertheless, how cells process DNA damage within lamina-associated domains (LADs), which reside in this environment, remains poorly understood, despite their relevance to nuclear architecture, aging, and senescence. By employing systems for temporally controlled and spatially precise induction of DNA double-strand breaks (DSBs) within LADs, we show that DSBs within LADs trigger remodeling of the nuclear lamina and the dynamic detachment of damaged LADs from the nuclear envelope, resulting in their relocalization to the nuclear interior. This process is orchestrated by the ATM/{gamma}H2AX/MDC1/RNF168/53BP1 axis and requires the linker of nucleoskeleton and cytoskeleton (LINC) complex and cytoskeletal components while leaving DNA repair pathway choice unchanged. Persistent tethering of damaged LADs at the nuclear periphery delays the DNA damage response and repair, elevates genomic instability, and drives chromatin extrusion through nuclear blebs directly linking failed repair to dysregulation of nuclear integrity. These findings reveal a protective mechanism in which ATM-driven LAD dynamics and nuclear envelope remodeling might relieve mechanical stress, facilitate repair, and safeguard both genome stability and nuclear architecture.

cell biology↗

bioRxiv2023

Inhibition of Topoisomerase 2 catalytic activity impacts the integrity of heterochromatin and repetitive DNA and leads to interlinks between clustered repeats

DNA replication and transcription generate DNA supercoiling, which can cause topological stress and intertwining of daughter chromatin fibers, posing challenges to the completion of DNA replication and chromosome segregation. Type II topoisomerases (Top2s) are enzymes that relieve DNA supercoiling and decatenate braided sister chromatids. How Top2 complexes deal with the topological challenges in different chromatin contexts, and whether all chromosomal contexts are subjected equally to torsional stress and require Top2 activity is unknown. Here we show that catalytic inhibition of the Top2 complex in interphase has a profound effect on the stability of heterochromatin and repetitive DNA elements. Mechanistically, we find that catalytically inactive Top2 is trapped around heterochromatin leading to DNA breaks and unresolved catenates, which necessitate the recruitment of the structure specific endonuclease, Ercc1-XPF, in an Slx4- and SUMO-dependent manner. Our data are consistent with a model in which Top2 complex resolves not only catenates between sister chromatids but also inter-chromosomal catenates between clustered repetitive elements.

cell biology↗

bioRxiv2023

Competition between transcription and loop extrusion modulates promoter and enhancer dynamics

The spatiotemporal configuration of genes with distal regulatory elements, and the impact of chromatin mobility on transcription, remain unclear. Loop extrusion is an attractive model for bringing genetic elements together, but how this functionally interacts with transcription is also largely unknown. We combine live tracking of genomic loci and nascent transcripts with molecular dynamics simulations to assess the 4D arrangement of the Sox2 gene and its enhancer, in response to a battery of perturbations. We find that alterations in chromatin mobility, not promoter-enhancer distance, is more informative about transcriptional status. Active elements display more constrained mobility, consistent with confinement within specialized nuclear sites, and alterations in enhancer mobility distinguish poised from transcribing alleles. Strikingly, we find that whereas loop extrusion and transcription factor-mediated clustering contribute to promoter-enhancer proximity, they have antagonistic effects on chromatin dynamics. This provides an experimental framework for the underappreciated role of chromatin dynamics in genome regulation.

cell biology↗

bioRxiv2019

Assessment of the Utility of Gene Positioning Biomarkers in the Stratification of Prostate Cancers

In eukaryotic cells, the genome is spatially organized in a non-random fashion within the confines of the interphase nucleus, and most genes occupy preferred nuclear positions. For some genomic loci these positioning patterns are context specific, reflected in the distinct location of certain genes and chromosomes in different cell types and in disease. Disease-related differential spatial positioning of genes has led to the hypothesis that the spatial reorganization of the genome may be utilized as a diagnostic biomarker. In keeping with this possibility, the positioning patterns of specific genes can be used to reproducibly discriminate benign tissues from cancerous ones. In addition to the use of spatial genome organization for diagnostic purposes, we explore here the potential use of spatial genome organization as a prognostic tool. This is a pressing need since in many cancer types there is a lack of accurate markers to predict the aggressiveness of individual tumors. We find that directional repositioning of SP100 and TGFB3 gene loci stratifies prostate cancers of differing Gleason scores. A more peripheral position of SP100 and TGFB3 in the nucleus, compared to benign tissues, is associated with low Gleason score cancers, whereas more internal positioning correlates with higher Gleason scores. Conversely, LMNA is more internally positioned in many non-metastatic prostate cancers, while its position is indistinguishable from benign tissue in metastatic cancer. Our findings of subtype-specific gene positioning patterns in prostate cancer provides a proof-of-concept for the potential usefulness of spatial gene positioning as a prognostic biomarker.

cancer biology↗