eLife assessment: Genome-wide mapping of native co-localized G4s and R-loops in living cells DOI Open Access
Andrés Aguilera

Published: July 22, 2024

The non-B DNA structures can act as dynamic functional genomic elements regulating gene expression. Among them, G4s and R-loops are two of the best studied. interplay between emerging in repair, replication transcription. A comprehensive picture native co-localized living cells is currently lacking. Here, we describe development HepG4-seq an optimized HBD-seq methods, which robustly capture R-loops, respectively, cells. We successfully employed these methods to establish maps human HEK293 mouse embryonic stem (mESCs). discovered that dynamically altered a cell type-dependent manner largely localized at active promoters enhancers transcriptional genes. further demonstrated helicase Dhx9 direct major regulator modulates formation resolution R-loops. Depletion impaired self-renewal differentiation capacities mESCs by altering transcription - associated Taken together, our work established endogenous prevalently persisted regulatory regions genes involved regulation their linked genes, opening door for exploring broader roles disease.

Language: Английский

Looping forward: exploring R‐loop processing and therapeutic potential DOI Creative Commons
Kalliopi Stratigi, Athanasios Siametis, George A. Garinis

et al.

FEBS Letters, Journal Year: 2024, Volume and Issue: unknown

Published: June 6, 2024

Recently, there has been increasing interest in the complex relationship between transcription and genome stability, with specific attention directed toward physiological significance of molecular structures known as R‐loops. These arise when an RNA strand invades into DNA duplex, their formation is involved a wide range regulatory functions affecting gene expression, repair processes or cell homeostasis. The persistent presence R‐loops, if not effectively removed, contributes to instability, underscoring factors responsible for resolution modification. In this review, we provide comprehensive overview how R‐loop processing can drive either beneficial harmful outcome. Additionally, explore potential manipulating such devise rationalized therapeutic strategies targeting aberrant accumulation

Language: Английский

Citations

4
Advancements and Challenges of R-loops in Cancers: Biological Insights and Future Directions DOI
Dengxiong Li, Fanglin Shao, Xinrui Li

et al.

Cancer Letters, Journal Year: 2024, Volume and Issue: 610, P. 217359 - 217359

Published: Nov. 27, 2024

Language: Английский

Citations

4
The hidden weavers: A review of DNA/RNA R-loops in stem cell biology and therapeutic potential DOI
Xu Chen,

Zizhao Mai,

Yucheng Zheng

et al.

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: 297, P. 139895 - 139895

Published: Jan. 14, 2025

Language: Английский

Citations

0
PLUNC downregulates the expression of PD-L1 by inhibiting the interaction of DDX17/β-catenin in nasopharyngeal carcinoma DOI Creative Commons
Ran-Ran Feng, Yilin Guo, Meilin Chen

et al.

Journal of Pathology and Translational Medicine, Journal Year: 2025, Volume and Issue: 59(1), P. 68 - 83

Published: Jan. 15, 2025

Background: Nasopharyngeal carcinoma (NPC) is characterized by high programmed death-ligand 1 (PD-L1) expression and abundant infiltration of non-malignant lymphocytes, which renders patients potentially suitable candidates for immune checkpoint blockade therapies. Palate, lung, nasal epithelium clone (PLUNC) inhibit the growth NPC cells enhance cellular apoptosis differentiation. Currently, relationship between PLUNC (as a tumor-suppressor) PD-L1 in unclear.Methods: We collected clinical samples to verify PD-L1. plasmid was transfected into cells, variation verified western blot immunofluorescence. In we PD-L1, activating transcription factor 3 (ATF3), β-catenin Later, further that regulates through β-catenin. Finally, effect on co-immunoprecipitation (Co-IP).Results: found lower tissues than paracancer tissues. opposite PLUNC. Western immunofluorescence showed could upregulate ATF3 while downregulate ATF3/PD-L1 inhibiting inhibits entry nucleus. Co-IP experiments demonstrated inhibited interaction DEAD-box helicase 17 (DDX17) β-catenin.Conclusions: downregulates DDX17/β-catenin NPC.

Language: Английский

Citations

0
Multi-modal investigation reveals pathogenic features of diverse DDX3X missense mutations DOI Creative Commons
Federica Mosti, Mariah L. Hoye, Carla F. Escobar-Tomlienovich

et al.

PLoS Genetics, Journal Year: 2025, Volume and Issue: 21(1), P. e1011555 - e1011555

Published: Jan. 21, 2025

De novo mutations in the RNA binding protein DDX3X cause neurodevelopmental disorders including syndrome and autism spectrum disorder. Amongst ~200 identified to date, half are missense. While loss of function is known impair neural cell fate, how landscape missense impacts neurodevelopment almost entirely unknown. Here, we integrate transcriptomics, proteomics, live imaging demonstrate clinically diverse perturb development via distinct cellular molecular mechanisms. Using mouse primary progenitors, investigate four recurrently mutated variants, spanning severe (2) mild (2). neurogenesis, have only a modest impact on fate. Moreover, expression leads profound neuronal death. proximity labeling screen discover variants unique interactors. We observe notable overlap amongst mutations, suggesting common mechanisms underlying altered fate survival. Transcriptomic analysis subsequent investigation highlights new pathways associated with upregulated DNA Damage Response. Notably, exhibit excessive damage neurons, increased cytoplasmic DNA:RNA hybrids formation stress granules. These findings highlight aberrant metabolism DDX3X-mediated In sum our reveal by which differentially neurodevelopment.

Language: Английский

Citations

0
A genome-wide association study identified 10 novel genomic loci associated with intrinsic capacity DOI

Melkamu Bedimo Beyene,

Renuka Visvanathan,

Robel Alemu

et al.

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

Published: Feb. 7, 2025

Abstract In 2015, the World Health Organization introduced concept of intrinsic capacity (IC), a composite all individual-level attributes that contribute to healthy aging. To investigate genetic basis IC, we used data from UK Biobank (UKB; N=44,631) and Canadian longitudinal study on aging (CLSA; N=13,085). We estimated SNP-based heritability (h 2 SNP ) at 25.2% in UKB 19.5% CLSA. A Genome-Wide Association Study (GWAS) identified 38 independent SNPs for IC across 10 genomic loci 4,289 candidate mapped 197 genes. Post-GWAS analysis revealed role these genes cellular processes such as cell proliferation, immune function, metabolism, neurodegeneration, with high expressions muscle, heart, brain, adipose, tibial nerve tissues. Of 52 traits tested, 23 showed significant correlations higher loading was associated scores. This is first identify variants pathways providing foundation future research

Language: Английский

Citations

0
The human HELQ helicase and XRN2 exoribonuclease cooperate in R-loop resolution DOI Creative Commons
Jinming Pan,

H. Betts,

Andrew Cubbon

et al.

Open Biology, Journal Year: 2025, Volume and Issue: 15(2)

Published: Feb. 1, 2025

The human HELQ helicase is a superfamily 2, 3′-5 homologous to POLQ and RNA helicases of the Ski2-like subfamily. It involved in diverse aspects DNA repair an emerging prognosis biomarker novel drug target for cancer therapy. interacts with RPA through its inherently disordered N-HELQ domain hence recruited RPA-bound substrates. Our study reveals role R-loop resolution. We show cells vitro that by at R-loops, which are then resolved if catalytically active as ATPase/helicase. Furthermore, we identify functional interaction XRN2, nuclear 5′ 3′ exoribonuclease, suggest coordinates unwinding digestion XRN2. Collectively, assign new biological function genome stability metazoans involvement XRN2 metabolism.

Language: Английский

Citations

0
Mechanisms underlining R-loop biology and implications for human disease DOI Creative Commons
Junzhe Liu,

Fengze Li,

Yulong Cao

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 13

Published: Feb. 21, 2025

R-loops are three-stranded non-canonical nucleic acid structures composed of nascent RNA hybridized with the template DNA strand, leaving non-template strand displaced. These play crucial roles in regulating gene expression, replication, and transcription processes. However, have also been increasingly described as highly deleterious, causing genomic instability damage. To maintain at a relatively safe level, complex regulatory mechanisms exist to prevent their excessive formation. The growing understanding R-loop functions has provided valuable insights into structure potential clinical applications. Emerging research indicates that contribute pathogenesis various disorders, including neurodegenerative, immune-related, neoplastic diseases. This review summarizes metabolism its significance etiology associated disorders. By elucidating governing R-loops, we aim establish theoretical foundation for disease exploring novel therapeutic strategies targeting these hybrid structures.

Language: Английский

Citations

0
SART3 promotes homologous recombination repair by stimulating DNA-RNA hybrids removal and DNA end resection DOI Creative Commons
Hui Fu, Min Huang, Honglin Wu

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 6, 2025

DNA-RNA hybrids triggered by double-strand breaks (DSBs) are crucial intermediates during DSB repair, and their timely resolution requires numbers of RNA helicases, including DEAD box 1 (DDX1). However, how these helicases recruited to DSB-induced in time remains largely unclear. Here, we revealed that squamous cell carcinoma antigen recognized T cells 3 (SART3) promotes DDX1 binding at DSBs for optimal homologous recombination (HR) repair. SART3 itself associates with PAR chains accumulates both PARylation- hybrids-dependent fashion. also is necessary enrichment DSBs. The defective SART3-DDX1 association observed expressing the cancer-associated variant SART3-R836W impairs not only accumulation DDX1, but hybrid removal HR efficiency. Moreover, DNA end resection through enhancing USP15-BARD1 BRCA1-BARD1 retention. Together, our study reveals an role rendering a promising target cancer therapy.

Language: Английский

Citations

0
Senataxin prevents replicative stress induced by the Myc oncogene DOI Creative Commons
Silvia Sberna, M. Filipuzzi,

Nicola Bianchi

et al.

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 19, 2025

Abstract Replicative stress (RS) is emerging as a promising therapeutic target in oncology, yet full exploitation of its potential requires detailed understanding the mechanisms and genes involved. Here, we investigated RNA helicase Senataxin (SETX), an enzyme that resolves RNA-DNA hybrids R-loops, to address role preventing RS by oncogenic Myc. Upon Myc activation, silencing SETX led selective engagement DNA damage response (DDR) robust cytotoxicity. Pharmacological dissection upstream kinases regulating DDR uncovered protective ATR pathway, once inhibited, boosted driven-DDR. While loss did not lead genome-wide increase mechanistic analyses revealed enhanced R-loops localized at DDR-foci newly replicated genomic loci, compatible with resolving alleviate Myc-induced RS. Genome-wide mapping double-strand breaks confirmed exacerbated transcription-replication conflict (TRC) regions early sites. We propose prevents TRCs transcription-associated encounter replisome. The identification genetic liability opens up new options against aggressive Myc-driven tumors.

Language: Английский

Citations

0