Replisomes restrict SMC-mediated DNA-loop extrusion in vivo

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 23, 2025

Abstract Structural maintenance of chromosomes (SMC) complexes organize genomes by extruding DNA loops, while replisomes duplicate entire chromosomes. These essential molecular machines must collide frequently in every cell cycle, yet how such collisions are resolved vivo remains poorly understood. Taking advantage the ability to load SMC at defined sites Bacillus subtilis genome, we engineered head-on and head-to-tail between replisome. Replisome progression was monitored marker frequency analysis, translocation time-resolved ChIP-seq Hi-C. We found that do not impede replisome progression. By contrast, restrict regardless collision orientations. Combining experimental data with simulations, determined blocked then released from chromosome. Occasionally, can bypass continue translocating. Our findings establish is a barrier SMC-mediated DNA-loop extrusion , implications for processes as chromosome segregation, repair, gene regulation require dynamic organization all organisms.

Язык: Английский

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DNA packaging by molecular motors: from bacteriophage to human chromosomes

Nature Reviews Genetics, Год журнала: 2024, Номер 25(11), С. 785 - 802

Опубликована: Июнь 17, 2024

Язык: Английский

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DCAF15 control of cohesin dynamics sustains acute myeloid leukemia

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Июль 3, 2024

The CRL4-DCAF15 E3 ubiquitin ligase complex is targeted by the aryl-sulfonamide molecular glues, leading to neo-substrate recruitment, ubiquitination, and proteasomal degradation. However, physiological function of DCAF15 remains unknown. Using a domain-focused genetic screening approach, we reveal as an acute myeloid leukemia (AML)-biased dependency. Loss results in suppression AML through compromised replication fork integrity consequent accumulation DNA damage. Accordingly, loss sensitizes stress-inducing therapeutics. Mechanistically, discover that directly interacts with SMC1A protein cohesin destabilizes regulatory factors PDS5A CDCA5. CDCA5 removal precludes acetylation on chromatin, resulting uncontrolled chromatin loop extrusion, defective replication, apoptosis. Collectively, our findings uncover endogenous, cell autonomous sustaining proliferation post-translational control dynamics.

Язык: Английский

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Heterozygous loss-of-function SMC3 variants are associated with variable growth and developmental features

Human Genetics and Genomics Advances, Год журнала: 2024, Номер 5(2), С. 100273 - 100273

Опубликована: Янв. 30, 2024

Heterozygous missense variants and in-frame indels in SMC3 are a cause of Cornelia de Lange syndrome (CdLS), marked by intellectual disability, growth deficiency, dysmorphism, via an apparent dominant-negative mechanism. However, the spectrum manifestations associated with loss-of-function has not been reported, leading to hypotheses alternative phenotypes or even developmental lethality. We used matchmaking servers, patient registries, other resources identify individuals heterozygous, predicted (pLoF) SMC3, analyzed population databases characterize mutational intolerance this gene. Here, we show that behaves as archetypal haploinsufficient gene: it is highly constrained against pLoF variants, strongly depleted for range phenotypes. Among 14 were variable but coalesced on low parameters, delay/intellectual reminiscent atypical CdLS. Comparisons missense/in-frame indel demonstrated overall milder presentation carriers. Furthermore, several harboring nonpenetrant growth, developmental, and/or dysmorphic features, some had symptomatologies rational biological links SMC3. Analyses tumor model system transcriptomic data epigenetic subset cases suggest reduce expression do support clustering functional genomic signatures typical Our finding substantial population-scale LoF concert features subjects expands scope cohesinopathies, informs their allelic architecture, suggests existence additional clearly LoF-constrained genes whose disease will be confirmed only multilayered paired careful phenotyping.

Язык: Английский

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Contributions of transcriptional noise to leukaemia evolution: KAT2A as a case-study

Philosophical Transactions of the Royal Society B Biological Sciences, Год журнала: 2024, Номер 379(1900)

Опубликована: Март 4, 2024

Transcriptional noise is proposed to participate in cell fate changes, but contributions mammalian differentiation systems, including cancer, remain associative. Cancer evolution driven by genetic variability, with modulatory or contributory participation of epigenetic variants. Accumulation variants enhances transcriptional noise, which can facilitate cancer transitions. Acute myeloid leukaemia (AML) an aggressive strong dependencies, characterized blocked differentiation. It constitutes attractive model probe links between and malignant regulation. Gcn5/KAT2A a classical regulator. Its loss increases modifies fates stem AML cells. By reviewing the analysis KAT2A-depleted pre-leukaemia models, I discuss that net result diversification secondary alternative programmes. Cellular enable hinder progression, respectively, types responsive mutations, maladaptation KAT2A-dependent noise-responsive genes ribosome biogenesis KAT2A destabilizes translational activity. putative perturbed translation biology, propose as for mechanistic integration control decisions. This article part discussion meeting issue ‘Causes consequences stochastic processes development disease’.

Язык: Английский

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