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Cohesin loop extrusion tethers DNA replication forks to drive their slowing and reversal

ABSTRACT: DNA replication forks challenged by genotoxic agents have a high degree of plasticity to ensure their stability, allowing replicative tolerance and complete genome duplication. How genome architectural factors influence this response is less understood. We have investigated the role of cohesin and its different functions by the use auxin-inducible degrons (AID) and separation of function mutants. With a newly-develop Micro-C based technique to capture chromatin contacts at nascent DNA (Repli-C), we describe that cohesin loop extrusion helps connecting adjacent replication forks belonging to different replication origins. This process promotes replication fork reversal by preventing unscheduled PrimPol action at replication forks. These findings reveal how tethering of distant replication fork influences fork plasticity and genome stability.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Orhi Barroso Gomila

LAB HEAD: Daniel González-Acosta

PROVIDER: PXD071150 | Pride | 2026-08-05

REPOSITORIES: Pride

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			Action	DRS
	20240603_C35244_003_S692947_NB_1_Group_1.raw	Raw
	20240603_C35244_005r_S692961_H100uMmA_3_Group_5.raw	Raw
	20240603_C35244_008_S692955_UmA_3_Group_3.raw	Raw
	20240603_C35244_009_S692966_H2mMmA_2_Group_7.raw	Raw
	20240603_C35244_011_S692950_Thy_1_Group_2.raw	Raw

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Cohesin loop extrusion tethers DNA replication forks to drive their slowing and reversal II

Project description:DNA replication forks challenged by genotoxic agents have a high degree of plasticity to ensure their stability, DNA damage tolerance and complete genome duplication. How genome architectural factors influence this response is poorly understood. Here, we investigated the role of cohesin and its different functions by the use of auxin-inducible degrons (AID) and separation of function mutants. With a newly-developed Micro-C based technique to capture chromatin contacts at nascent DNA (Repli-C), we describe that loop-extruding cohesin helps tethering replication forks in proximal chromosomal regions, including those departed from adjacent replication origins. Replication stress strengthens these contacts by promoting cohesin stabilization at forks. This process promotes replication fork reversal and active fork slowing, by preventing PRIMPOL action on ssDNA. These findings reveal how cohesin loop extrusion, mainly implicated in genome organization, is employed upon replication stress to restrict fork progression, mediating fork plasticity and protecting genome stability.

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Cohesin loop extrusion tethers DNA replication forks to drive their slowing and reversal

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Dynamics of de novo heterochromatin assembly and disassembly at replication forks ensures fork stability

Project description:Chromatin is dynamically reorganized when DNA replication forks are challenged. However, the process of epigenetic reorganization and its implication for fork stability is poorly understood. Here, we discover a checkpoint regulated cascade of chromatin signaling that activates 5 the histone methyltransferase EHMT2/G9a to catalyze heterochromatin assembly at stressed replication forks. Using biochemical and single molecule chromatin fiber approaches, we show that G9a together with SUV39h1 induces chromatin compaction by accumulating the repressive modifications, H3K9me1/me2/me3, in the vicinity of stressed replication forks. This closed conformation is also favored by the G9a-dependent exclusion of the H3K9-demethylase 10 JMJD1A/KDM3A, which facilitates heterochromatin disassembly upon fork restart. Untimely heterochromatin disassembly from stressed forks by KDM3A enables PRIMPOL access, triggering ssDNA gap formation and sensitizing cells towards chemotherapeutic drugs. These findings may help explaining chemotherapy resistance and poor prognosis observed in cancer patients displaying elevated level of G9a/H3K9me3.

2023-05-12 | PXD041742 | Pride

Cohesin association to replication sites depends on Rad50 and promotes fork restart

Project description:The cohesin complex holds together newly-replicated chromatids and is involved in diverse pathways that preserve genome integrity. We show that in budding yeast, cohesin is transiently recruited to active replication origins and it spreads along DNA as forks progress. When DNA synthesis is impeded, cohesin accumulates at replication sites and is critical for the recovery of stalled forks. Cohesin enrichment at replication forks does not depend on H2A(X) formation, which differs from its loading requirements at DNA double-strand breaks (DSBs). However, cohesin localization is largely reduced in rad50delta mutants and cells lacking both Mec1 and Tel1 checkpoint kinases. Interestingly, cohesin loading at replication sites depends on the structural features of Rad50 that are important for bridging sister chromatids, including the CXXC hook domain and the length of the coiled-coil extensions. Together, these data reveal a novel function for cohesin in the maintenance of genome integrity during S phase. Scc1 ChIP, Rad50 ChIP and BrdU IP in wild type and mutants at different stages of the cell cycle.

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DONSON encodes a novel replication fork protection factor mutated in 2 microcephalic dwarfism.

Project description:To ensure efficient genome duplication, cells have evolved a multitude of factors that promote unperturbed DNA replication, and protect, repair and restart damaged forks. Here we identify DONSON as a novel fork protection factor, and report biallelic DONSON mutations in individuals with microcephalic dwarfism. We demonstrate that DONSON is a component of the replisome that stabilises forks during normal genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATR-dependent ,signalling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity, and potentiating chromosomal instability. Hypomorphic mutations substantially reduce DONSON protein levels and impair fork stability in patient cells, consistent with defective DNA replication underlying the disease phenotype In summary, we identify mutations in DONSON as a common cause of microcephalic dwarfism, and establish DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability

2017-03-28 | MSV000080704 | MassIVE

Proteome dynamics at stalled replication forks reveal a coordinated recruitment of repair factors

Project description:The faithful replication of DNA is a fundamental cellular process that ensures the transfer of genetic information during cell division. Genome duplication takes place during S phase and requires the dynamic and coordinated recruitment of multiple proteins at the replication forks. The instability and collapse of the replication fork can occur when cells are exposed to different genotoxic stresses, which can be overcome by the action of DNA repair pathways. Studying the proteomic interactions implicated in those events is thus a crucial step in understanding the complex biological mechanisms involved in DNA replication and repair. Proximity-dependent biotinylation coupled with mass spectrometry identification of proteins (BioID2) was used on 17 proteins from four different complexes known to play a role during DNA replication and repair to study the assembly and recruitment of proteins at stalled replication forks caused by treatment with hydroxyurea. This analysis revealed a vast interaction network of 108 proteins modulated in the presence of hydroxyurea; 45 being enriched and 63 depleted. Interestingly, 11 of them were found to be both enriched and depleted depending on the complex considered, suggesting a dynamic reorganization of the players and their interactions (?). Furthermore, the analysis identified several poorly characterized proteins, thus uncovering new players in the cellular response to DNA replication arrest. Overall, this collection of replication fork proteomes enables large-scale identification of the mechanisms of assembly and disassembly of protein complexes at the sites of stalled replication forks and provides a new framework to understand how cells respond to obstacles on DNA template, causing fork stalling or collapse.

2026-02-04 | PXD037136 | Pride

Changes in replisome composition underlie the rewiring of DNA replication during embryonic stem cell reprogramming

Project description:Pluripotent stem cells can give rise to the three embryonic germ layers and the characterization of their properties is crucial to exploit their therapeutic potential. Mouse embryonic stem cells (mESCs) are isolated and usually maintained in vitro in a primed state that resembles the post-implantation epiblast features. Furthermore, primed mESCs can be de-differentiated to a naive state that resembles the pre-implantation inner cell mass (ICM). Cell differentiation or genotoxic stress, among others, can alter DNA replication, which is a flexible process able to adapt to different cellular contexts. Here, we demonstrate that primed-to-naive mESC reprogramming triggers replication fork slowdown, increased fork asymmetry and a compensatory activation of dormant origins. Using iPOND (“isolation of proteins on nascent DNA”) coupled to mass spectrometry we have characterized the changes in replisome composition between naive and primed mESCs. Several DNA repair factors, including MRE11 nuclease, are enriched in naive mESCs forks, while factors involved in ubiquitin-dependent protein metabolism are enriched in primed mESC forks. We report that primed-to-naive mESC de-differentiation promotes recruitment of MRE11 to the forks in response to transcription-replication conflicts, underlying the DNA replication rewiring required for efficient mESC reprogramming.

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DONSON encodes a novel replication fork protection factor mutated in 2 microcephalic dwarfism.

2017-02-10 | PXD005690 | Pride

DONSON encodes a novel replication fork protection factor mutated in microcephalic dwarfism.

Project description:To ensure efficient genome duplication, cells have evolved a multitude of factors that promote unperturbed DNA replication, and protect, repair and restart damaged forks. Here we identify DONSON as a novel fork protection factor, and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a component of the replisome that stabilises forks during normal genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATR-dependent signalling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity, and potentiating chromosomal instability. Hypomorphic mutations substantially reduce DONSON protein levels and impair fork stability in patient cells, consistent with defective DNA replication underlying the disease phenotype. In summary, we identify mutations in DONSON as a common cause of microcephalic dwarfism, and establish DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.

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Cohesin and cohesion establishment factors distribution on S.Cerevisiae chromosome VI during the cell cycle

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