Looping forward: exploring R‐loop processing and therapeutic potential

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

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

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

Published: Nov. 27, 2024

Language: Английский

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Transketolase attenuates the chemotherapy sensitivity of glioma cells by modulating R-loop formation

Cell Reports, Journal Year: 2025, Volume and Issue: 44(1), P. 115142 - 115142

Published: Jan. 1, 2025

Highlights•TKT attenuates the chemosensitivity in glioma independent of catalytic activity•Chemotherapeutic drugs promote TKT's nuclear translocation cells•TKT interacts with XRN2 to regulate resolution and removal R-loopsSummaryGlioblastoma (GBM) is a highly lethal malignant brain tumor poor survival rates, chemoresistance poses significant challenge treatment patients GBM. Here, we show that transketolase (TKT), metabolic enzyme pentose phosphate pathway (PPP), chemotherapy sensitivity cells manner activity. Mechanistically, chemotherapeutic can facilitate TKT protein from cytosol into nucleus, where physically R-loops. Depletion leads increased R-loop accumulation genome instability, increasing susceptibility chemotherapy. In conclusion, our study reveals non-metabolic function regulating dynamics, gliomas.Graphical abstract

Language: Английский

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SART3 promotes homologous recombination repair by stimulating DNA-RNA hybrids removal and DNA end resection

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

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Histone Phosphorylation in DNA Damage Response

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(6), P. 2405 - 2405

Published: March 7, 2025

The DNA damage response (DDR) is crucial for maintaining genomic stability and preventing the accumulation of mutations that can lead to various diseases, including cancer. DDR a complex cellular regulatory network involves sensing, signal transduction, repair, cell cycle arrest. Modifications in histone phosphorylation play important roles these processes, facilitating repair factor recruitment, chromatin remodeling, regulation. precise regulation critical effective damage, integrity maintenance, prevention diseases such as cancer, where mechanisms are often compromised. Thus, understanding provides insights into offers potential therapeutic targets associated with instability, cancers.

Language: Английский

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KRT80, Regulated by RNF8-Mediated Ubiquitination, Contributes to Glucose Metabolic Reprogramming and Progression of Glioblastoma

Neurochemical Research, Journal Year: 2025, Volume and Issue: 50(2)

Published: March 27, 2025

Language: Английский

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Nuclear‐Localized BCKDK Facilitates Homologous Recombination Repair to Support Breast Cancer Progression and Therapy Resistance

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: April 29, 2025

Abstract Homologous recombination repair (HRR) is crucial for maintaining genomic stability by repairing DNA damage. Despite its importance, HRR's role in cancer progression not fully elucidated. Here, this work shows that nuclear‐localized branched‐chain α‐ketoacid dehydrogenase kinase (BCKDK) acts as a modulator of HRR, promoting cell resistance against damage‐inducing therapy breast cancer. Mechanistically, demonstrates BCKDK localized the nucleus and phosphorylates RNF8 at Ser157, preventing ubiquitin‐mediated degradation RAD51, thereby facilitating HRR‐mediated under replication stress. Notably, aberrant expression BCKDK/p‐RNF8/RAD51 axis correlates with poor patient survival. Furthermore, identifies small molecule inhibitor BCKDK, GSK180736A, disrupts HRR function exhibits strong tumor suppression when combined drugs. Collectively, study reveals new regulating independent metabolic function, presenting it potential therapeutic target predictive biomarker

Language: Английский

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Molecular Basis of XRN2-Deficient Cancer Cell Sensitivity to Poly(ADP-ribose) Polymerase Inhibition

Cancers, Journal Year: 2024, Volume and Issue: 16(3), P. 595 - 595

Published: Jan. 30, 2024

R-loops (RNA–DNA hybrids with displaced single-stranded DNA) have emerged as a potent source of DNA damage and genomic instability. The termination defective RNA polymerase II (RNAPII) is one the major sources R-loop formation. 5′-3′-exoribonuclease 2 (XRN2) promotes genome-wide efficient RNAPII termination, XRN2-deficient cells exhibit increased emanating from elevated R-loops. Recently, we showed that instigated by XRN2 depletion in human fibroblast resulted enhanced poly(ADP-ribose) 1 (PARP1) activity. Additionally, established synthetic lethal relationship between PARP1. However, underlying cellular stress response promoting this lethality remains elusive. Here, delineate molecular consequences leading to cancer induced PARP inhibition. We found lung breast display sensitivity two clinically relevant inhibitors, Rucaparib Olaparib. At mechanistic level, inhibition combined deficiency exacerbates double-strand break formation cells. Consistent our previous findings using several different siRNAs, also show hyperactivates Furthermore, observed replication treated inhibitors. Finally, compromised PARP1 catalytic function activates caspase-3 initiate cell death. Collectively, these provide insights into strengthen translational implications for targeted therapy.

Language: Английский

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Nucleolar Pol II interactome reveals TBPL1, PAF1, and Pol I at intergenic rDNA drive rRNA biogenesis

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

Published: Nov. 6, 2024

Ribosomal DNA (rDNA) repeats harbor ribosomal RNA (rRNA) genes and intergenic spacers (IGS). polymerase (Pol) I transcribes rRNA yielding components of ribosomes. IGS-associated Pol II prevents from excessively synthesizing IGS non-coding RNAs (ncRNAs) that can disrupt nucleoli production. Here, compartment-enriched proximity-dependent biotin identification (compBioID) revealed the TATA-less-promoter-binding TBPL1 transcription-regulatory PAF1 with nucleolar II. localizes to TCT motifs, driving maintaining its baseline ncRNA levels. promotes elongation, preventing unscheduled R-loops hyper-restrain I-associated ncRNAs. or deficiency disrupts organization biogenesis. In PAF1-deficient cells, repressing rescues Depleting I-dependent ncRNAs is sufficient compromise nucleoli. We present interactome show regulation by ensures structure function. By revealing II, authors transcription within DNA's levels critical

Language: Английский

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Nucleolar Pol II interactome reveals TBPL1, PAF1, and Pol I at intergenic rDNA drive rRNA biogenesis

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 10, 2023

Abstract Nucleolar ribosomal DNA (rDNA) repeats control ribosome manufacturing. rDNA harbors a RNA (rRNA) gene and an intergenic spacer (IGS). polymerase (Pol) I transcribes rRNA genes yielding the components of ribosomes. Pol II at IGS induces production by preventing from excessively synthesizing non-coding RNAs (ncRNAs) that can disrupt nucleoli. At IGS, regulatory processes whether function be beneficial remain unknown. Here, we identify regulators, uncovering nucleolar optimization via I. Compartment-enriched proximity-dependent biotin identification (compBioID) showed enrichment TATA-less promoter-binding TBPL1 transcription regulator PAF1 with II. localizes to TCT motifs, driving maintaining its baseline ncRNA levels. promotes elongation, unscheduled R-loops hyper-restrain ncRNAs. or deficiency disrupts organization biogenesis. In PAF1-deficient cells, repressing rescues production. Depleting I-dependent ncRNAs is sufficient compromise We present interactome show ensures structure operation.

Language: Английский

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