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Lamin A/C restrains replication domain activity through higher-order chromatin structures and PCNA interaction [CUT&Tag]

ABSTRACT: Lamin A/C, a critical nuclear lamina protein, is essential for maintaining nuclear architecture, organizing chromatin and preserving genomic stability. However, its role in directly regulating DNA replication remains unclear. This study investigates how Lamin A/C orchestrates replication initiation by modulating chromatin structure and interacting with proliferating cell nuclear antigen (PCNA). Utilizing high-resolution imaging, chromatin accessibility assays, and sequencing, we demonstrate that Lamin A/C stabilizes replication domains (RDs) by restricting chromatin mobility, preserving spatial organization, and maintaining accessibility. Furthermore, Lamin A/C interacts with PCNA via its Ig-fold domain, regulating PCNA availability by sequestering a pool of PCNA and modulating its expression, and thereby controlling its recruitment to replication machinery. The loss of Lamin A/C results in chromatin architecture reorganization and elevated PCNA availability at RDs, which coordinately trigger excessive activation of replication origins, leading to replication stress and DNA damage. These disruptions prolong the S phase and compromise genome stability, highlighting Lamin A/C as a critical gatekeeper of balanced replication initiation. Our findings reveal Lamin A/C’s dual role in chromatin organization and replication machinery regulation, offering valuable insights into its involvement in replication-associated diseases such as cancer and viral infections and highlighting potential therapeutic opportunities through targeting replication dynamics.

ORGANISM(S): Homo sapiens

PROVIDER: GSE289475 | GEO | 2025/02/22

REPOSITORIES: GEO

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Lamin A/C restrains replication domain activity through higher-order chromatin structures and PCNA interaction [ATAC-Seq]

Project description:Lamin A/C, a critical nuclear lamina protein, is essential for maintaining nuclear architecture, organizing chromatin and preserving genomic stability. However, its role in directly regulating DNA replication remains unclear. This study investigates how Lamin A/C orchestrates replication initiation by modulating chromatin structure and interacting with proliferating cell nuclear antigen (PCNA). Utilizing high-resolution imaging, chromatin accessibility assays, and sequencing, we demonstrate that Lamin A/C stabilizes replication domains (RDs) by restricting chromatin mobility, preserving spatial organization, and maintaining accessibility. Furthermore, Lamin A/C interacts with PCNA via its Ig-fold domain, regulating PCNA availability by sequestering a pool of PCNA and modulating its expression, and thereby controlling its recruitment to replication machinery. The loss of Lamin A/C results in chromatin architecture reorganization and elevated PCNA availability at RDs, which coordinately trigger excessive activation of replication origins, leading to replication stress and DNA damage. These disruptions prolong the S phase and compromise genome stability, highlighting Lamin A/C as a critical gatekeeper of balanced replication initiation. Our findings reveal Lamin A/C’s dual role in chromatin organization and replication machinery regulation, offering valuable insights into its involvement in replication-associated diseases such as cancer and viral infections and highlighting potential therapeutic opportunities through targeting replication dynamics.

2025-02-22 | GSE289473 | GEO

Lamin A/C restrains replication domain activity through higher-order chromatin structures and PCNA interaction [BRU-Seq]

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Polycomb dysfunctional transcriptional repression in muscle stem cells contributes to lamin dependent muscular dystrophy [ChIP-seq]

Project description:Polycomb group of proteins (PcG) and the nuclear Lamin A are key factors in the maintenance of chromatin higher order structures required for preserving cell identity. Mutations in the Lamin A/C gene cause several diseases, belonging to the class of laminopathies, including Emery-Dreifuss Muscular Dystrophy. Nevertheless, epigenetic mechanisms involved in the pathogenesis of lamin-dependent dystrophy are still largely unknown. We show that Lamin A loss causes deregulated PcG positioning in muscular stem cells followed by upregulation of adipogenic markers and induction of the senescence’s driver p16INK4a from Cdkn2a locus. This aberrant transcriptional programme causes impairment in self-renewal, loss of cell identity and premature exhaustion of quiescent satellite cell pool. Genetic ablation of Cdkn2a locus restores muscle growth and muscle stem cell properties in Lamin A/C null dystrophic mice. In conclusion, our findings suggest that Lamin A has an essential role in preserving satellite cell self-renewal capacity and indicate that Lamin A-dependent muscular dystrophy can be ascribed to intrinsic epigenetic dysfunctions of muscle stem cells

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Polycomb dysfunctional transcriptional repression in muscle stem cells contributes to lamin dependent muscular dystrophy [RNA-seq]

2020-02-04 | GSE123723 | GEO

Identification of Elg1 interaction partners and effects on post-replication chromatin re-formation

Project description:Elg1, the major subunit of a Replication Factor C-like complex, is critical to ensure genomic stability during DNA replication, and is implicated in controlling chromatin structure. We investigated the consequences of Elg1 loss for the dynamics of chromatin re-formation following DNA replication. Measurement of Okazaki fragment length and the micrococcal nuclease sensitivity of newly replicated DNA revealed a defect in nucleosome re-assembly in the absence of Elg1. Using a proteomic approach to identify Elg1 binding partners, we discovered that Elg1 interacts with Rtt106, a histone chaperone implicated in replication-coupled nucleosome assembly that also regulates transcription. We find that Rtt106 recruitment to a number of promoters depends on Elg1. A central role for Elg1 is the unloading of PCNA from chromatin following DNA replication, so we examined the relative importance of Rtt106 and PCNA unloading for chromatin reassembly following DNA replication. We find that the major cause of the chromatin assembly defects of an elg1 mutant is PCNA retention on DNA following replication, with Rtt106-Elg1 interaction potentially playing a contributory role.

2018-10-31 | E-MTAB-6985 | biostudies-arrayexpress

The g-tubulin meshwork assists to the transport of cytosolic PCNA to chromatin in mammalian cells

Project description:Changes in the location of g-tubulin ensure cell survival and preserve genome integrity. We investigated whether the nuclear accumulation of g-tubulin facilitates the transport of proliferating cell nuclear antigen (PCNA) between the cytosolic and the nuclear compartment in mammalian cells. We found that the g-tubulin meshwork assists to the recruitment of PCNA to chromatin. Also, decreased levels of g-tubulin reduce the nuclear pool of PCNA. In addition, the g-tubulin C terminus encodes a PCNA-interacting peptide (PIP) motif, and a g-tubulin–PIP-mutant affects the nuclear accumulation of PCNA. In a cell-free system, PCNA and g-tubulin formed a complex. In tumors, there is a significant positive correlation between TUBG1 and PCNA expression. Thus, we report a novel mechanism that constitutes the basis for tumor growth by which the g-tubulin meshwork maintains indefinite proliferation by acting as an opportune scaffold for the transport of PCNA from the cytosol to the chromatin.

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The g-tubulin meshwork assists to the transport of cytosolic PCNA to chromatin in mammalian cells

Project description:Changes in the location of g-tubulin ensure cell survival and preserve genome integrity. We investigated whether the nuclear accumulation of g-tubulin facilitates the transport of proliferating cell nuclear antigen (PCNA) between the cytosolic and the nuclear compartment in mammalian cells. We found that the g-tubulin meshwork assists to the recruitment of PCNA to chromatin. Also, decreased levels of g-tubulin affected the nuclear pool of PCNA. In addition, the g-tubulin C terminus encodes a PCNA-interacting peptide (PIP) motif, and a g-tubulin–PIP-mutant affects the nuclear accumulation of PCNA. In a cell-free system, PCNA and g-tubulin formed a complex. In tumors, there is a significant positive correlation between TUBG1 and PCNA expression. Thus, we report a novel mechanism that constitutes the basis for tumor growth by which the g-tubulin meshwork maintains indefinite proliferation by acting as an opportune scaffold for the transport of PCNA from the cytosol to the chromatin.

2021-06-18 | GSE173732 | GEO

Autophagy mediates degradation of nuclear lamina

Project description:Autophagy is a catabolic membrane trafficking process involved in degradation of cellular constituents through lysosomes, which maintains cell and tissue homeostasis. While much attention has been focused on autophagic turnover of cytoplasmic materials, little is known regarding the role of autophagy in degrading nuclear components. Here we report that autophagy machinery mediates degradation of nuclear lamina in mammalian cells, a process we term laminophagy. The autophagy protein LC3 is present in the nucleus and directly interacts with the nuclear lamina protein Lamin B1, and associates with lamin-associated domains (LADs) on chromatin. This interaction does not downregulate Lamin B1 during starvation, but mediates nuclear lamina degradation upon tumorigenic insults, such as by oncogenic Ras. Laminophagy is achieved by nucleus-to-cytosol transport that delivers Lamin B1 to lysosome for degradation. Inhibiting autophagy or LC3-Lamin B1 interaction prevents oncogenic Ras-induced Lamin B1 loss and delays oncogene-induced cell cycle arrest. Our study unveils a role of autophagy in degrading nuclear materials, and suggests laminophagy as a guarding mechanism protecting cells from tumorigenesis.

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Nuclear peripheral chromatin-lamin B1 interaction is required for global integrity of chromatin architecture and dynamics in human cells

Project description:Background: The eukaryotic genome is folded into higher-order conformation accompanied with constrained dynamics for coordinated genome functions. However, the molecular machinery underlying these hierarchically organized three-dimensional (3D) chromatin architecture and dynamics remains poorly understood. Results: Here by combining imaging and sequencing, we studied the role of lamin B1 in chromatin architecture and dynamics. We found that lamin B1 depletion leads to chromatin redistribution and decompaction. Consequently, lamina-associated domains (LADs) are detached from the nuclear periphery. The inter-chromosomal interactions and overlap between chromosome territories are increased. Moreover, Hi-C data revealed that lamin B1 is required for the integrity and segregation of chromatin compartments but not for the topologically associating domains (TADs). Using live cell single molecule tracking, we further proved that depletion of lamin B1 leads to increased chromatin dynamics, owing to chromatin decompaction and redistribution toward nucleoplasm. Conclusions: Taken together, our data suggest that lamin B1 and chromatin interactions at the nuclear periphery promote LAD maintenance, genomic compartmentalization into chromosome territories and A/B compartments and confine chromatin dynamics, supporting its crucial role in chromatin higher-order structure and chromatin dynamics.

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Involvement of a chromatin remodeling complex in damage tolerance during DNA replication

Project description:ATP-dependent chromatin remodeling complexes have been shown to participate in DNA replication in addition to transcription and DNA repair. However, the mechanisms of their involvement in DNA replication remain unclear. Here, we reveal a specific function of the yeast INO80 chromatin remodeling complex in the DNA damage tolerance pathways. Whereas INO80 is necessary for the resumption of replication at forks stalled by methyl methane sulfonate (MMS), it is not required for replication fork collapse after treatment with hydroxyurea (HU). Mechanistically, INO80 regulates DNA damage tolerance during replication through modulation of PCNA (proliferating cell nuclear antigen) ubiquitination and Rad51-mediated processing of recombination intermediates at impeded replication forks. Our findings establish a mechanistic link between INO80 and DNA damage tolerance pathways, indicating that chromatin remodeling is important for accurate DNA replication. INO80 distribution in WT cells was measured.

2010-06-20 | E-GEOD-18570 | biostudies-arrayexpress

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