Helicases in R-loop Formation and Resolution

Journal of Biological Chemistry, Journal Year: 2023, Volume and Issue: 299(11), P. 105307 - 105307

Published: Sept. 29, 2023

With the development and wide usage of CRISPR technology, presence R-loop structures, which consist an RNA–DNA hybrid a displaced single-strand (ss) DNA, has become well accepted. structures have been implicated in variety circumstances play critical roles metabolism nucleic acid relevant biological processes, including transcription, DNA repair, telomere maintenance. Helicases are enzymes that use ATP-driven motor force to unwind double-strand (ds) dsRNA, or hybrids. Additionally, certain helicases strand-annealing activity. Thus, possess unique positions for biogenesis: they utilize their activity promote hybridization RNA leading formation R-loops; conversely, unwinding separate hybrids resolve R-loops. Indeed, numerous such as senataxin (SETX), Aquarius (AQR), WRN, BLM, RTEL1, PIF1, FANCM, ATRX (alpha-thalassemia/mental retardation, X-linked), CasDinG, several DEAD/H-box proteins reported while other helicases, Cas3 UPF1, stimulate formation. Moreover, like DDX1, DDX17, DHX9 identified both resolution. In this review, we will summarize latest understandings regarding metabolism. highlight challenges associated with drug discovery context targeting these helicases. R-loops three-stranded consisting single-stranded DNA. They various transcriptional regulation replication, genomic instability, class switch recombination B cells, damage maintenance (1Brickner J.R. Garzon J.L. Cimprich K.A. Walking tightrope: complex balancing act genome stability.Mol. Cell. 2022; 82: 2267-2297Google Scholar, 2Petermann E. Lan L. Zou Sources, resolution physiological relevance RNA-DNA hybrids.Nat. Rev. Mol. Cell Biol. 23: 521-540Google 3Hegazy Y.A. Fernando C.M. Tran E.J. The biology: good, bad, ugly.J. Chem. 2020; 295: 905-913Google 4Niehrs C. Luke B. Regulatory facilitators gene expression stability.Nat. 21: 167-178Google 5Garcia-Muse T. Aguilera A. 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Language: Английский

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R-loop and diseases: the cell cycle matters

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: April 27, 2024

Abstract The cell cycle is a crucial biological process that involved in growth, development, and reproduction. It can be divided into G1, S, G2, M phases, each period closely regulated to ensure the production of two similar daughter cells with same genetic material. However, many obstacles influence cycle, including R-loop formed throughout this process. triple-stranded structure, composed an RNA: DNA hybrid single strand, which ubiquitous organisms from bacteria mammals. existence has important significance for regulation various physiological processes. aberrant accumulation due its limited resolving ability will detrimental cells. For example, damage genomic instability, caused by R-loop, activate checkpoints turn induce arrest death. At present, growing number factors have been proven prevent or eliminate thereby avoiding mutations. Therefore, we need gain detailed insight resolution at different stages cycle. In review, review current knowledge play role as well how mutations these lead onset progression diseases.

Language: Английский

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RNA polymerase II associates with active genes during DNA replication

Nature, Journal Year: 2023, Volume and Issue: 620(7973), P. 426 - 433

Published: July 19, 2023

Language: Английский

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R-Loops in Genome Instability and Cancer

Cancers, Journal Year: 2023, Volume and Issue: 15(20), P. 4986 - 4986

Published: Oct. 14, 2023

R-loops are unique, three-stranded nucleic acid structures that primarily form when an RNA molecule displaces one DNA strand and anneals to the complementary in a double-stranded molecule. R-loop formation can occur during natural processes, such as transcription, which nascent remains hybridized with template strand, while non-template is displaced. However, also arise due many non-natural including damage, dysregulation of degradation pathways, defects processing. Despite their prevalence throughout whole genome, predominantly found actively transcribed gene regions, enabling serve seemingly controversial roles. On hand, pathological accumulation contributes genome instability, hallmark cancer development plays role tumorigenesis, progression, therapeutic resistance. other play critical roles regulating essential expression, chromatin organization, class-switch recombination, mitochondrial replication, repair. In this review, we summarize discoveries related formation, suppression, removal influence on repair, oncogenic events. We have discussed therapeutical opportunities by targeting R-loops.

Language: Английский

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RNA biogenesis and RNA metabolism factors as R-loop suppressors: a hidden role in genome integrity

Genes & Development, Journal Year: 2024, Volume and Issue: unknown

Published: July 10, 2024

Genome integrity relies on the accuracy of DNA metabolism, but as appreciated for more than four decades, transcription enhances mutation and recombination frequencies. More recent research provided evidence a previously unforeseen link between RNA which is often related to accumulation DNA–RNA hybrids R-loops. In addition physiological roles, R-loops interfere with replication repair, providing molecular scenario origin genome instability. Here, we review current knowledge multiple factors that prevent or resolve consequent transcription–replication conflicts thus act modulators dynamics.

Language: Английский

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Replication–Transcription Conflicts: A Perpetual War on the Chromosome

Annual Review of Biochemistry, Journal Year: 2024, Volume and Issue: 93(1), P. 21 - 46

Published: April 10, 2024

DNA replication and transcription occur in all living cells across domains of life. Both essential processes simultaneously on the same template, leading to conflicts between macromolecular machines that perform these functions. Numerous studies over past few decades demonstrate this is an inevitable problem both prokaryotic eukaryotic cells. We have learned lead fork reversal, breaks DNA, R-loop formation, topological stress, mutagenesis can ultimately impact evolution. Recent also provided insight into various mechanisms mitigate, resolve, allow tolerance how result pathological consequences divergent species. In review, we summarize our current knowledge regarding outcomes encounters machineries explore clashes are dealt with

Language: Английский

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RNF8 ubiquitylation of XRN2 facilitates R-loop resolution and restrains genomic instability in BRCA1 mutant cells

Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 51(19), P. 10484 - 10505

Published: Aug. 24, 2023

Breast cancer linked with BRCA1/2 mutations commonly recur and resist current therapies, including PARP inhibitors. Given the lack of effective targeted therapies for BRCA1-mutant cancers, we sought to identify novel targets selectively kill these cancers. Here, report that loss RNF8 significantly protects Brca1-mutant mice against mammary tumorigenesis. deficiency in human breast cells was found promote R-loop accumulation replication fork instability, leading increased DNA damage, senescence, synthetic lethality. Mechanistically, interacts XRN2, which is crucial transcription termination resolution. We ubiquitylates XRN2 facilitate its recruitment R-loop-prone genomic loci decreases occupancy at sites, thereby promoting accumulation, transcription-replication collisions, excessive cell death. Collectively, our work identifies a lethal interaction between BRCA1, mediated by pathological R-loops.

Language: Английский

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Bacterial homologs of innate eukaryotic antiviral defenses with anti-phage activity highlight shared evolutionary roots of viral defenses

Cell Host & Microbe, Journal Year: 2024, Volume and Issue: 32(8), P. 1427 - 1443.e8

Published: Aug. 1, 2024

Language: Английский

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Senataxin RNA/DNA helicase promotes replication restart at co-transcriptional R-loops to prevent MUS81-dependent fork degradation

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(17), P. 10355 - 10369

Published: Aug. 9, 2024

Abstract Replication forks stalled at co-transcriptional R-loops can be restarted by a mechanism involving fork cleavage-religation cycles mediated MUS81 endonuclease and DNA ligase IV (LIG4), which presumably relieve the topological barrier generated transcription-replication conflict (TRC) facilitate ELL-dependent reactivation of transcription. Here, we report that restart R-loop-stalled replication via MUS81-LIG4-ELL pathway requires senataxin (SETX), helicase unwind RNA:DNA hybrids. We found SETX promotes progression preventing R-loop accumulation during S-phase. Interestingly, loss activity leads to nascent degradation upon induction R-loop-mediated stalling hydroxyurea. This phenotype is independent reversal results from DNA2-mediated resection MUS81-cleaved accumulate due defective restart. Finally, demonstrate acts in common with DEAD-box DDX17 suppress stress human cells. A possible cooperation between these RNA/DNA helicases unwinding TRC sites discussed.

Language: Английский

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Senataxin deficiency disrupts proteostasis through nucleolar ncRNA-driven protein aggregation

The Journal of Cell Biology, Journal Year: 2024, Volume and Issue: 223(7)

Published: May 8, 2024

Senataxin is an evolutionarily conserved RNA-DNA helicase involved in DNA repair and transcription termination that associated with human neurodegenerative disorders. Here, we investigated whether loss affects protein homeostasis based on previous work showing R-loop-driven accumulation of damage aggregates cells. We find results the insoluble proteins, including many factors known to be prone aggregation These are located primarily nucleolus promoted by upregulation non-coding RNAs expressed from intergenic spacer region ribosomal DNA. also map sites R-loop cells lacking higher hybrids within DNA, peri-centromeric regions, other but not at annotated protein-coding genes. findings indicate solubility proteome through regulation transcription-dependent lesions nucleus nucleolus.

Language: Английский

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