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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Steinmetz al.Yeast Sen1 protects instability.Mol. 41: 21-32Google 149Alzu Bermejo Begnis Lucca Piccini Carotenuto al.Senataxin associates forks fork across RNA-polymerase-II-transcribed genes.Cell. 151: 835-846Google Scholar)AQR√Splicing factorAka IBP160(150Sollier Stork C.T. Garcia-Rubio M.L. Paulsen Transcription-coupled nucleotide excision R-loop-induced 2014; 777-785Google Scholar)UPF1Upf1√Nonsense mRNA surveillance(31Ngo Scholar)PIF1Rrm3, ScPif1, SpPfh1√Genomic nucleus mitochondriaS. cerevisiae members: Rrm3 ScPif1; pombe one: Pfh1(151Tran P.L.T. Pohl T.J. C.F. Chan Pott Zakian family suppress mediated tRNA genes.Nat. 2017; 815025Google Scholar)SF2WRN√Werner syndrome(63Marabitti Lillo Malacaria Palermo Sanchez Pichierri al.ATM pathway activation limits Werner cells.Nucleic 47: 3485-3502Google Scholar)BLMSgs1√Bloom syndrome(65Chang E.Y. Novoa C.A. Aristizabal M.J. Segovia Chaturvedi al.RECQ-like Sgs1 regulate instability.J. 216: 3991-4005Google Scholar)RTEL1√Telomere shorteningInteracts Poldip3(68Bjorkman Johansen S.L. Schertzer Kanellis D.C. Katsori A.M. Poldip3 responses resolution.Genes Dev. 34: 1065-1074Google Scholar)FANCMMph1√Congenital abnormalities, pancytopenia, infertility, cancer proneness(70Schwab R.A. Nieminuszczy Shah Langton Lopez Martinez Liang C.C. al.The fanconi maintains coordinating transcription.Mol. 60: 351-361Google 71Hodson van Twest Dylewska O'Rourke Tan Murphy V.J. al.Branchpoint translocation remodelers general mechanism removal.Cell 41111749Google 152Lafuente-Barquero Graf Lockhart Smc5/6 Mph1 hybrid-mediated 13e1007136Google Scholar)Polymerase θ (POLQ)√Xeroderma PigmentosumHelicase domain (1–894 aa) unwinds vitro(73Ozdemir A.Y. Rusanov Kent Siddique Pomerantz R.T. Polymerase theta-helicase efficiently 293: 5259-5269Google Scholar)CasDinG (Bacteria)√(74Domgaard Cahoon Armbrust Redman O. Jolley Thomas al.CasDinG 5'-3' dsDNA three accessory domains IV immunity.Nucleic 8115-8132Google 75Cui X.Y. al.Type IV-A CRISPR-Csf complex: assembly, targeting, recruitment.Mol. 83: 2493-2508.e2495Google Scholar)SNF2ATRXRad54√ATRX syndromeA recent report shows unable Scholar)(72Nguyen D.T. Voon H.P.J. Xella Scott Clynes Babbs chromatin remodelling suppresses telomeric repeats.EMBO 18: 914-928Google Scholar)SMARCAL1√Schimke Immunoosseous DysplasiaAka HARP, helicase(71Hodson 153Yusufzai Kadonaga HARP helicase.Science. 2008; 322: 748-750Google Scholar)ZRANB3√African-specific diabetesAka (AH2)(71Hodson Scholar)DEAD-boxDDX1√√Retinoblastoma neuroblastoma(100Li Germain D.R. Po

Language: Английский

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The epilepsy–autism phenotype associated with developmental and epileptic encephalopathies: New mechanism‐based therapeutic options

Epilepsia, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 22, 2025

Abstract Epilepsy and autism often co‐occur in genetic developmental epileptic encephalopathies (DEEs), but their underlying neurobiological processes remain poorly understood, complicating treatment. Advances molecular genetics understanding the neurodevelopmental pathogenesis of epilepsy–autism phenotype may lead to mechanism‐based treatments for children with DEEs autism. Several genes, including newly reported PPFIA3 , MYCBP2 DHX9 TMEM63B RELN are linked various disorders, intellectual disabilities, autistic features. These findings underscore clinical heterogeneity suggest diverse mechanisms influenced by genetic, epigenetic, environmental factors. Mechanisms linking epilepsy include γ‐aminobutyric acidergic (GABAergic) signaling dysregulation, synaptic plasticity, disrupted functional connectivity, neuroinflammatory responses. GABA system abnormalities, critical inhibitory neurotransmission, contribute both conditions. Dysregulation mechanistic target rapamycin (mTOR) pathway neuroinflammation also pivotal, affecting seizure generation, drug resistance, neuropsychiatric comorbidities. Abnormal function connectivity further phenotype. New treatment options targeting specific emerging. Genetic variants potassium channel genes like KCNQ2 KCNT1 frequent causes early onset DEEs. Personalized retigabine quinidine have been explored heterogeneous Efforts ongoing develop more effective KCNQ activators blockers. SCN1A variants, particularly Dravet syndrome, show potential symptoms low‐dose clonazepam, fenfluramine, cannabidiol, although human trials yet consistently replicate animal model successes. Early intervention before age 3 years, ‐ tuberous sclerosis complex‐related DEEs, is crucial. Additionally, mTOR shows promise control managing epilepsy‐associated Understanding distinct spectrum disorder implementing behavioral interventions essential improving outcomes. Despite advances, significant challenges persist diagnosing treating DEE‐associated phenotypes. Future should adopt precision health approaches improve

Language: Английский

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Functional genomics and small molecules in mitochondrial neurodevelopmental disorders

Neurotherapeutics, Journal Year: 2024, Volume and Issue: 21(1), P. e00316 - e00316

Published: Jan. 1, 2024

Mitochondria are critical for brain development and homeostasis. Therefore, pathogenic variation in the mitochondrial or nuclear genome which disrupts function frequently results developmental disorders neurodegeneration at organismal level. Large-scale application of genome-wide technologies to individuals with diseases has dramatically accelerated identification disease-gene associations humans. Multi-omic high-throughput studies involving transcriptomics, proteomics, metabolomics, saturation editing providing deeper insights into functional consequence genomic variation. Integration deep phenotypic data through allelic series continues uncover novel functions permit gene dissection on an unprecedented scale. Finally, illuminate disease mechanisms thereby direct therapeutic strategies small molecules RNA-DNA therapeutics. This review summarizes progress genomics molecule therapeutics neurodevelopmental disorders.

Language: Английский

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The 2024 version of the gene table of neuromuscular disorders (nuclear genome)

Neuromuscular Disorders, Journal Year: 2023, Volume and Issue: 34, P. 126 - 170

Published: Dec. 14, 2023

Language: Английский

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DHX9 SUMOylation is required for the suppression of R-loop-associated genome instability

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 17, 2024

Abstract RNA helicase DHX9 is essential for genome stability by resolving aberrant R-loops. However, its regulatory mechanisms remain unclear. Here we show that SUMOylation at lysine 120 (K120) crucial function. Preventing K120 leads to R-loop dysregulation, increased DNA damage, and cell death. Cells expressing K120R mutant which cannot be SUMOylated are more sensitive genotoxic agents this sensitivity mitigated RNase H overexpression. Unlike the mutant, wild-type interacts with R-loop-associated proteins such as PARP1 DDX21 via SUMO-interacting motifs. Fusion of SUMO2 enhances association these proteins, reduces accumulation, alleviates survival defects K120R. Our findings highlight critical role in maintaining regulating protein interactions necessary balance.

Language: Английский

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DEAD/DEAH-box RNA helicases shape the risk of neurodevelopmental disorders

Trends in Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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GA4GH Phenopacket-Driven Characterization of Genotype-Phenotype Correlations in Mendelian Disorders

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 6, 2025

ABSTRACT Comprehensively characterizing genotype-phenotype correlations (GPCs) in Mendelian disease would create new opportunities for improving clinical management and understanding biology. However, heterogeneous approaches to data sharing, reuse, analysis have hindered progress the field. We developed Genotype Phenotype Evaluation of Statistical Association (GPSEA), a software package that leverages Global Alliance Genomics Health (GA4GH) Phenopacket Schema represent case-level genetic about individuals. GPSEA applies an independent filtering strategy boost statistical power detect categorical GPCs represented by Human Ontology terms. additionally enables visualization continuous phenotypes, severity scores, survival such as age onset or manifestations. applied 85 cohorts with 6613 previously published individuals variants one 80 genes associated 122 diseases identified 225 significant GPCs, 48 having at least statistically GPC. These results highlight standardized representations scalable discovery disease.

Language: Английский

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Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a severe developmental disorder spectrum

Genetics in Medicine, Journal Year: 2024, Volume and Issue: 27(1), P. 101273 - 101273

Published: Sept. 19, 2024

Language: Английский

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Evolutionarily Conserved DHX9/MLE Helicase Is Involved in the Regulation of Its Own mRNA Expression Level in Drosophila melanogaster

Doklady Biochemistry and Biophysics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

Language: Английский

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Maf-family bZIP transcription factor NRL interacts with RNA-binding proteins and R-loops in retinal photoreceptors

Published: Feb. 13, 2025

RNA-binding proteins (RBPs) perform diverse functions including the regulation of chromatin dynamics and coupling transcription with RNA processing. However, our understanding their actions in mammalian neurons remains limited. Using affinity purification, yeast-two-hybrid proximity ligation assays, we identified interactions multiple RBPs NRL, a Maf-family bZIP factor critical for retinal rod photoreceptor development function. In addition to splicing, many NRL-interacting are associated R-loops, which form during increase maturation. Focusing on DHX9 helicase, demonstrate that its expression is modulated by NRL NRL-DHX9 interaction positively influenced R-loops. ssDRIP-Seq analysis reveals both stranded unstranded R-loops at distinct genomic elements, characterized active inactive epigenetic signatures enriched neuronal genes. binds types suggesting an epigenetically independent Our findings suggest additional highlight complex among factors, RBPs, regulating gene retina.

Language: Английский

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