Replication stress as a driver of cellular senescence and aging

Communications Biology, Год журнала: 2024, Номер 7(1)

Опубликована: Май 22, 2024

Abstract Replication stress refers to slowing or stalling of replication fork progression during DNA synthesis that disrupts faithful copying the genome. While long considered a nexus for damage, role in aging is under-appreciated. The consequential promotion organismal phenotypes evidenced by an extensive list hereditary accelerated disorders marked molecular defects factors promote and operate uniquely response. Additionally, recent studies have revealed cellular pathways elicited align with designated hallmarks aging. Here we review advances demonstrating as ultimate driver senescence We discuss clinical implications intriguing links between including application senotherapeutic approaches context stress.

Язык: Английский

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G-quadruplex–stalled eukaryotic replisome structure reveals helical inchworm DNA translocation

Science, Год журнала: 2025, Номер 387(6738)

Опубликована: Март 6, 2025

DNA G-quadruplexes (G4s) are non-B-form secondary structures that threaten genome stability by impeding replication. To elucidate how G4s induce replication fork arrest, we characterized collisions with preformed in the parental using reconstituted yeast and human replisomes. We demonstrate a single G4 leading strand template is sufficient to stall replisomes arresting CMG helicase. Cryo-electron microscopy of stalled complexes reveal folded lodged inside central channel, translocation. The stabilizes at distinct translocation intermediates, suggesting an unprecedented helical inchworm mechanism for These findings illuminate eukaryotic under normal perturbed conditions.

Язык: Английский

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Elevated reactive oxygen species can drive the alternative lengthening of telomeres pathway in ATRX-null cancers

Nucleic Acids Research, Год журнала: 2025, Номер 53(4)

Опубликована: Янв. 27, 2025

The alternative lengthening of telomeres (ALT) pathway is a telomerase-independent mechanism for immortalization in cancer cells and commonly activated low-grade high-grade glioma, as well osteosarcoma. ALT can be under various conditions has often been shown to include mutational loss ATRX. However, this insufficient isolation so other cellular event must also implicated. It that excessive accumulation DNA:RNA hybrid structures (R-loops) and/or formation DNA-protein crosslinks (DPCs) important driving factors. underlying events leading R-loop DPC date remain unclear. Here, we demonstrate reactive oxygen species (ROS) an causative factor the evolution ALT-telomere maintenance ATRX-deficient glioma. We identified three sources elevated ROS ALT-positive gliomas: co-mutation SETD2, downregulation DRG2, hypoxic tumour microenvironment. leads R-loops and, crucially, resolution by enzyme RNase H1 prevents activity exposed ROS. Further, found possible causal link between DPCs, particular, TOP1 complexes covalently linked DNA (Top1cc). elevation trigger over-activity osteosarcoma glioma cell lines, resulting damage death. This work presents mechanistic insights into endogenous origin DPCs cancers, highlighting potential novel therapeutic approaches these difficult-to-treat types.

Язык: Английский

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Transcription-replication conflicts drive R-loop-dependent nucleosome eviction and require DOT1L activity for transcription recovery

Nucleic Acids Research, Год журнала: 2025, Номер 53(4)

Опубликована: Фев. 8, 2025

Progressing transcription and replication machineries profoundly impact their underlying chromatin template. Consequently, transcription-replication conflict (TRC) sites are vulnerable to epigenome alterations, provoking genome instability. Here, we engineered an inducible TRC reporter system using a genome-integrated R-loop-prone sequence characterized the dynamic changes of local structure inflicted by TRCs, leading reduced nucleosome occupancy fork blockage. Strikingly, inducing small number TRCs on results in measurable global stress response. Furthermore, find TRC-dependent increase H3K79 methylation specifically at R-loop forming site. Accordingly, inhibition methyltransferase DOT1L leads transcriptional output exacerbated DNA damage response, suggesting that deposition this mark is required for effective recovery resolution TRCs. Our work shows molecular dynamics reveals specific epigenetic modifier bookmarking sites, relevant cancer other diseases.

Язык: Английский

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DNA-RNA hybrids in inflammation: sources, immune response, and therapeutic implications

Journal of Molecular Medicine, Год журнала: 2025, Номер unknown

Опубликована: Март 25, 2025

Язык: Английский

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Advancements and Challenges of R-loops in Cancers: Biological Insights and Future Directions

Cancer Letters, Год журнала: 2024, Номер 610, С. 217359 - 217359

Опубликована: Ноя. 27, 2024

Язык: Английский

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Clues to transcription/replication collision‐induced DNA damage: it was RNAP, in the chromosome, with the fork

FEBS Letters, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 24, 2024

DNA replication and RNA transcription processes compete for the same template and, thus, frequently collide. These transcription–replication collisions are thought to lead genomic instability, which places a selective pressure on organisms avoid them. Here, we review predisposing causes, molecular mechanisms, downstream consequences of (TRCs) with strong emphasis prokaryotic model systems, before contrasting findings cases in eukaryotic systems. Current research points structure as primary determinant steady‐state TRC levels polymerase regulation inducer excess TRCs. We proposed mechanisms TRC‐induced damage, attempting clarify their mechanistic requirements. Finally, discuss what drives genomes select against

Язык: Английский

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Pathological R-loops in bacteria from engineered expression of endogenous antisense RNAs whose synthesis is ordinarily terminated by Rho

Nucleic Acids Research, Год журнала: 2024, Номер 52(20), С. 12438 - 12455

Опубликована: Сен. 12, 2024

In many bacteria, the essential factors Rho and NusG mediate termination of synthesis nascent transcripts (including antisense RNAs) that are not being simultaneously translated. It has been proposed in Rho's absence toxic RNA-DNA hybrids (R-loops) may be generated from untranslated transcripts, genome-wide mapping studies Escherichia coli have identified putative loci R-loop formation more than 100 endogenous synthesized only a Rho-deficient strain. Here we provide evidence engineered expression wild-type E. several such individual regions on plasmid or chromosome generates R-loops that, an RNase H-modulated manner, serve to disrupt genome integrity. inhibition was associated with increased prevalence also Xanthomonas oryzae pv. Caulobacter crescentus. Our results confirm role bacterial genera for prevention pervasive yet cryptic transcripts. Engineered R-looped useful both site-specific impediments chromosomal replication mechanisms their resolution.

Язык: Английский

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RNA Polymerase II is a Polar Roadblock to a Progressing DNA Fork

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Окт. 13, 2024

DNA replication and transcription occur simultaneously on the same template, leading to inevitable conflicts between replisome RNA polymerase. These can stall fork threaten genome stability. Although numerous studies show that head-on are more detrimental prone promoting R-loop formation than co-directional conflicts, fundamental cause for polymerase roadblock polarity remains unclear, structure of these R-loops is speculative. In this work, we use a simple model system address complex question by examining Pol II advanced via mechanical unzipping mimic progression. We found binds stably resist removal in configuration, even with minimal transcript size, demonstrating has an inherent polarity. However, elongating long becomes potent persistent while retaining polarity, RNA-DNA hybrid mediates enhancement. Surprisingly, discovered when collides backtracked, form lagging strand front II, creating topological lock traps at fork. TFIIS facilitates severing connection hybrid. further demonstrate prime T7 still bound DNA. Our findings capture basal properties interactions fork, revealing significant implications transcription-replication conflicts.

Язык: Английский

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The hidden architects of the genome: a comprehensive review of R-loops

Molecular Biology Reports, Год журнала: 2024, Номер 51(1)

Опубликована: Окт. 26, 2024

Язык: Английский

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