DNA-PKcs-dependent phosphorylation of RECQL4 promotes NHEJ by stabilizing the NHEJ machinery at DNA double-strand breaks

Nucleic Acids Research, Год журнала: 2022, Номер 50(10), С. 5635 - 5651

Опубликована: Май 3, 2022

Non-homologous end joining (NHEJ) is the major pathway that mediates repair of DNA double-strand breaks (DSBs) generated by ionizing radiation (IR). Previously, helicase RECQL4 was implicated in promoting NHEJ, but its role remains unresolved. In this study, we report stabilizes NHEJ machinery at DSBs to promote repair. Specifically, find interacts with core factor DNA-PKcs and interaction increased following IR. promotes bridging mediated Ku70/80 vitro accumulation/retention factors vivo. Moreover, between other proteins IR treatment attenuated absence RECQL4. These data indicate stabilization support formation long-range synaptic complex. addition, observed kinase activity required for accumulation phosphorylates six serine/threonine residues. Blocking phosphorylation these sites reduced recruitment DSBs, factors, destabilized interactions machinery, resulted decreased NHEJ. Collectively, illustrate reciprocal regulation

Язык: Английский

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Neuronal Populations Involved in Motor Function Show Prominent Expression of Sbno1 During Postnatal Brain Development

Journal of Developmental Biology, Год журнала: 2025, Номер 13(1), С. 3 - 3

Опубликована: Янв. 21, 2025

Human genome studies have suggested that strawberry notch homologue 1 (SBNO1) is crucial for normal brain development, with mutations potentially contributing to neurodevelopmental disorders. In a previous study, we observed significant developmental abnormalities in the neocortex of Sbno1 as early one week after birth. present conducted an extensive analysis postnatal expression C57BL/6 mice using newly developed in-house polyclonal antibody against Sbno1. We found expressed all neurons, certain neuronal populations exhibiting distinct dynamic changes (both temporal and spatial) level. These findings suggest developmentally regulated They also indicate while may play general role across it serve more specialized functions types and/or cellular activities related particular pathways.

Язык: Английский

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Structural basis of RECQL5-induced RNA polymerase II transcription braking and subsequent reactivation

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

Опубликована: Янв. 31, 2025

Abstract During productive transcription elongation, the speed of RNA polymerase II (Pol II) is highly dynamic within individual genes and varies between different 1,2 . Unregulated rapid elongation can lead to detrimental consequences such as transcription-replication collisions, altered alternative splicing patterns, genome instability 1–7 Therefore, elongating Pol requires mechanisms slow its progression, yet molecular basis braking remains unclear. RECQL5 a DNA helicase that functions general factor by slowing down 8–11 Here we report cryo-electron microscopy (cryo-EM) structures human bound multiple complexes. Combined with biochemical analysis, identify an α-helix responsible for binding slowdown elongation. We further reveal transcription-coupled repair (TCR) complex allows overcome RECQL5-induced through concerted actions translocase activity competition engaging II. Additionally, inhibits TCR-mediated ubiquitination prevent activation pathway. Our results suggest model in which TCR coordinately regulate rate ensure efficiency while maintaining stability. This work provides framework future studies on regulatory role gene expression.

Язык: Английский

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4(3H)-Quinazolinone: A Natural Scaffold for Drug and Agrochemical Discovery

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(6), С. 2473 - 2473

Опубликована: Март 10, 2025

4(3H)-quinazolinone is a functional scaffold that exists widely both in natural products and synthetic organic compounds. Its drug-like derivatives have been extensively synthesized with interesting biological features including anticancer, anti-inflammatory, antiviral, antimalarial, antibacterial, antifungal, herbicidal, etc. In this review, we highlight the medicinal agrochemical versatility of according to studies published past six years (2019–2024), comprehensively give summary target recognition, structure–activity relationship, mechanism its analogs. The present review expected provide valuable guidance for discovering novel lead compounds containing moiety drug research.

Язык: Английский

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Analysis of germline-somatic mutational connections in colorectal cancer reveals differential tumorigenic patterns and a novel predictive marker for germline mutation carriers

Cancer Letters, Год журнала: 2025, Номер unknown, С. 217637 - 217637

Опубликована: Март 1, 2025

Язык: Английский

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During recombinase-mediated homology recognition RecQ helicases inhibit formation of toxic long-lived D-loops that could promote genomic instability

Nucleic Acids Research, Год журнала: 2025, Номер 53(9)

Опубликована: Май 10, 2025

Abstract Mutations in RecQ family helicases underlie human genetic disorders associated with genomic instability and cancer predisposition, but questions remain about how properly functioning reduces these deleterious effects. Importantly, some of the effects may result from incorrect repair DNA double-strand breaks (DSBs) by recombinase proteins. Displacement loops (D-loops) are three-strand intermediates formed recombinases during DSB. might enhance genome stability disassembling recombinase-mediated D-loops between mismatched sequences and/or short regions accidental homology. We used bulk FRET gel electrophoresis assays to probe context ongoing D-loop formation. found that does not differentially promote disassembly or include base pairs. Thus, reduce discriminating against D-loops. In contrast, our results suggest intervenes formation limit length Without intervention, can become so long they do spontaneously reverse. prevents undesirable long-lived connections chromosomes could compromise chromosome metabolism segregation instability.

Язык: Английский

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Bloom Syndrome Helicase Compresses Single‐Stranded DNA into Phase‐Separated Condensates

Angewandte Chemie International Edition, Год журнала: 2022, Номер 61(39)

Опубликована: Авг. 4, 2022

Abstract Bloom syndrome protein (BLM) is a conserved RecQ family helicase involved in the maintenance of genome stability. BLM has been widely recognized as “caretaker” that processes structured DNA. In contrast, our knowledge how behaves on single‐stranded (ss) DNA still limited. Here, we demonstrate possesses intrinsic ability for phase separation and can co‐phase separate with ssDNA to form dynamically arrested protein/ssDNA co‐condensates. The introduction ATP potentiates capability condense ssDNA, which further promotes compression against resistive force up 60 piconewtons. Moreover, also capable condensing replication A (RPA)‐ or RAD51‐coated before it generates naked by dismantling these ssDNA‐binding proteins. Overall, findings identify an unexpected characteristic provide new angle co‐condensation understanding genomic instability caused overexpression under diseased conditions.

Язык: Английский

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Research on Werner Syndrome: Trends from Past to Present and Future Prospects

Genes, Год журнала: 2022, Номер 13(10), С. 1802 - 1802

Опубликована: Окт. 6, 2022

A rare and autosomal recessive premature aging disorder, Werner syndrome (WS) is characterized by the early onset of aging-associated diseases, including shortening stature, alopecia, bilateral cataracts, skin ulcers, diabetes, osteoporosis, arteriosclerosis, chromosomal instability, as well cancer predisposition. WRN, gene responsible for WS, encodes DNA helicase with a 3′ to 5′ exonuclease activity, numerous studies have revealed that WRN involved in maintenance chromosome stability through actions DNA, e.g., replication, repair, recombination, epigenetic regulation via interaction repair factors, telomere-binding proteins, histone modification enzymes, other metabolic factors. However, although these efforts elucidated cellular functions cell lines, they not been linked treatment disease. Life expectancy has improved WS patients over past three decades, it hoped fundamental disease will be developed. Disease-specific induced pluripotent stem (iPS) cells established, are expected used drug discovery regenerative medicine patients. In this article, we review trends research date present some perspectives on regard application cells. Furthermore, elucidation mechanisms utilizing vast amount scientific data accumulated discussed.

Язык: Английский

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Helicase: A genetic tool for providing stress tolerance in plants

Plant Stress, Год журнала: 2023, Номер 9, С. 100171 - 100171

Опубликована: Июнь 3, 2023

Alteration of stress (abiotic and biotic) constitutes one the major problems for normal plants health. In present scenario, new molecular tools are broadly utilized to improve tolerance high-yielding crop plants. Helicases such proteins that as largest conserved gene families in eukaryotes, prokaryotes, All members this family involved DNA RNA metabolism inside cell which maintains cellular functions. Environmental reduces plant's growth yield causes severe global food losses. To overcome stress-inducing losses, a stress-tolerant trait is required security. process nucleic acid act potential molecules abiotic Both helicase highly influences defense mechanism protects from pathogen infection other factors Helicase enzyme classified into six superfamilies SF1 SF6. protein acts motor. uses energy nucleoside 5′-triphosphate (NTP) unwinding energetic stable duplex single strands. helicases have some common properties. Those binding, hydrolysis, NTP ds 3′ 5′ or direction. mainly plants' nuclei, mitochondria, chloroplasts. But recently researchers found plant an important role develop healthy high yielding under stressful environments. Unlike helicase, large group biochemical activities, including unwinding, displacement RNA, strand annealing. DEAD-box metabolisms like review, we summarized discussed structure, function, different crops.

Язык: Английский

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Exploring the Structures and Functions of Macromolecular SLX4-Nuclease Complexes in Genome Stability

Frontiers in Genetics, Год журнала: 2021, Номер 12

Опубликована: Ноя. 4, 2021

All organisms depend on the ability of cells to accurately duplicate and segregate DNA into progeny. However, is frequently damaged by factors in environment from within cells. One most dangerous lesions a double-strand break. Unrepaired breaks are major driving force for genome instability. Cells contain sophisticated repair networks counteract harmful effects genotoxic agents, thus safeguarding integrity. Homologous recombination high-fidelity, template-dependent pathway essential accurate nicks, gaps breaks. Accurate homologous depends remove branched structures that form during repair, which achieved through opposing actions helicases structure-selective endonucleases. This review focuses endonuclease called SLX1-SLX4 macromolecular complexes assemble SLX4 scaffold. First, we discuss recent developments illuminate structure biochemical properties this somewhat atypical endonuclease. We then summarize multifaceted roles fulfilled human its associated endonucleases stability. Finally, work SLX4-binding proteins may represent integral components these nuclease complexes, emphasizing function protein SLX4IP.

Язык: Английский

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