Redox regulation: mechanisms, biology and therapeutic targets in diseases

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: March 7, 2025

Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment, profoundly influencing both onset progression of various diseases. Under physiological conditions, oxidative free radicals generated by mitochondrial respiratory chain, endoplasmic reticulum, NADPH oxidases can be effectively neutralized NRF2-mediated antioxidant responses. These responses elevate synthesis superoxide dismutase (SOD), catalase, well key molecules like nicotinamide adenine dinucleotide phosphate (NADPH) glutathione (GSH), thereby maintaining cellular redox homeostasis. Disruption this finely tuned equilibrium is closely linked to pathogenesis wide range Recent advances have broadened our understanding molecular mechanisms underpinning dysregulation, highlighting pivotal roles genomic instability, epigenetic modifications, protein degradation, metabolic reprogramming. findings provide foundation for exploring regulation mechanistic basis improving therapeutic strategies. While antioxidant-based therapies shown early promise conditions where stress plays primary pathological role, efficacy diseases characterized complex, multifactorial etiologies remains controversial. A deeper, context-specific signaling, particularly redox-sensitive proteins, designing targeted aimed at re-establishing balance. Emerging small molecule inhibitors that target specific cysteine residues proteins demonstrated promising preclinical outcomes, setting stage forthcoming clinical trials. In review, we summarize current intricate relationship disease also discuss how these insights leveraged optimize strategies practice.

Language: Английский

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A di-acetyl-decorated chromatin signature couples liquid condensation to suppress DNA end synapsis

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(7), P. 1206 - 1223.e15

Published: Feb. 28, 2024

Language: Английский

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Structural insights into the activation of ataxia-telangiectasia mutated by oxidative stress

Science Advances, Journal Year: 2023, Volume and Issue: 9(39)

Published: Sept. 27, 2023

Ataxia-telangiectasia mutated (ATM) is a master kinase regulating DNA damage response that activated by double-strand breaks. However, ATM also directly reactive oxygen species, but how oxidative activation achieved remains unknown. We determined the cryo-EM structure of an H2O2-activated and showed under oxidizing conditions, formed intramolecular disulfide bridge between two protomers are rotated relative to each other when compared basal state. This rotation accompanied release substrate-blocking PRD region twisting N-lobe C-lobe, which greatly optimizes catalysis. active site remodeling enabled us capture substrate (p53) bound enzyme. provides first structural insights into during stress.

Language: Английский

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Structure and mechanism in non-homologous end joining

DNA repair, Journal Year: 2023, Volume and Issue: 130, P. 103547 - 103547

Published: July 29, 2023

DNA double-stranded breaks (DSBs) are a particularly challenging form of damage to repair because the damaged must not only undergo chemical reactions responsible for returning it its original state, but, additionally, two free ends can become physically separated in nucleus and be bridged prior repair. In nonhomologous end joining (NHEJ), one major pathways DSB repair, is carried out by number factors capable binding directly ends. It has been unclear how these processes at molecular level, owing part lack structural evidence describing coordination NHEJ with each other substrate. Advances cryo-Electron Microscopy (cryo-EM), allowing characterization large protein complexes that would intractable using techniques, have led visualization several key steps process, which support model sequential assembly DSB, followed end-bridging mediated protein-protein transition full synapsis. Here we examine models, devoting particular attention recent work identifying new intermediate state incorporating into general mechanism. We also discuss evolving understanding mechanisms DNA-PKcs's role mediating

Language: Английский

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Secrets of DNA-PKcs beyond DNA repair

npj Precision Oncology, Journal Year: 2024, Volume and Issue: 8(1)

Published: July 23, 2024

Abstract The canonical role of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) in repairing DNA double-strand breaks combined with its reported dysregulation several malignancies has driven development DNA-PKcs inhibitors as therapeutics. However, until recently relationship between and tumorigenesis been primarily investigated regard to non-homologous end joining (NHEJ) repair. Emerging research uncovered non-canonical functions involved transcriptional regulation, telomere maintenance, metabolic immune signaling all which may also impinge on tumorigenesis. This review mainly discusses these roles cellular biology their potential contribution tumorigenesis, well evaluating implications targeting for cancer therapy.

Language: Английский

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Overview of Roles of Novel Components in the Regulation of DNA Damage Repair in BRCA1-Deficient Cancers: An Update

DNA, Journal Year: 2025, Volume and Issue: 5(2), P. 17 - 17

Published: April 1, 2025

Cancers that arise from germline mutations of breast cancer associated gene 1 (BRCA1), which is a crucial player in homologous recombination (HR) DNA repair, are vulnerable to DNA-damaging agents such as platinum and PARP inhibitors (PARPis). Increasing evidence suggests BRCA1 an essential driver all phases the cell cycle, thereby maintaining orderly steps during cycle progression. Specifically, loss activity causes S-phase, G2/M, spindle checkpoints, centrosome duplication be dysregulated, blocking proliferation inducing apoptosis. In vertebrates, HR genes and/or BRCA2 lethal, since prerequisite for genome integrity. Thus, cells utilize alternative repair pathways non-homologous end joining (NHEJ) cope with function. this review, we attempt update discuss how these novel components regulating damage (DDR) BRCA1-deficient cancers.

Language: Английский

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Medicinal chemistry breakthroughs on ATM, ATR, and DNA-PK inhibitors as prospective cancer therapeutics

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 40(1)

Published: April 21, 2025

This review discusses the critical roles of Ataxia Telangiectasia Mutated Kinase (ATM), ATM and Rad3-related (ATR), DNA-dependent protein kinase (DNA-PK) in DNA damage response (DDR) their implications cancer. Emphasis is placed on intricate interplay between these kinases, highlighting collaborative distinct maintaining genomic integrity promoting tumour development under dysregulated conditions. Furthermore, covers ongoing clinical trials, patent literature, medicinal chemistry campaigns ATM/ATR/DNA-PK inhibitors as antitumor agents. Notably, employed robust drug design strategies aimed at assembling new structural templates with amplified DDR inhibitory ability, well outwitting pharmacokinetic liabilities existing inhibitors. Given success attained through such endeavours, pipeline repair anticipated to be supplemented by a reasonable number tractable entries (DDR inhibitors) soon.

Language: Английский

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ER-associated degradation ligase HRD1 links ER stress to DNA damage repair by modulating the activity of DNA-PKcs

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(37)

Published: Sept. 3, 2024

Proteostasis and genomic integrity are respectively regulated by the endoplasmic reticulum-associated protein degradation (ERAD) DNA damage repair signaling pathways, with both pathways essential for carcinogenesis drug resistance. How these coordinate each other remains unexplored. We found that ER stress specifically induces DNA-PKcs-regulated nonhomologous end joining (NHEJ) pathway to amend impede cell death. Intriguingly, sustained rapidly decreased activity of DNA-PKcs accumulated, facilitating a switch from adaptation This inactivation was caused increased KU70/KU80 degradation. Unexpectedly, ERAD ligase HRD1 efficiently destabilize classic nuclear HDAC1 in cytoplasm, catalyzing HDAC1's polyubiquitination at lysine 74, late stage stress. By abolishing HDAC1-mediated deacetylation, transmits signals nucleus. The resulting enhanced acetylation provides binding sites E3 TRIM25, promotion proteins. Both vitro vivo cancer models showed genetic or pharmacological inhibition HADC1 sensitizes colon cells inducers, including Food Drug Administration-approved celecoxib. antitumor effects combined approach were also observed patient-derived xenograft models. These findings identify mechanistic link between cytoplasm nucleus, indicating anticancer strategies may be developed induce severe while simultaneously inhibiting KU70/KU80/DNA-PKcs-mediated NHEJ signaling.

Language: Английский

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Synthesis, X-ray Crystal Structure, Anticancer, Hirshfeld Surface Analysis, DFT, TD-DFT, ADMET, and Molecular Docking of 3-Phenyl-1,2,4-triazolo[3,4-h]-13,4-thiaza-11-crown-4

Molecules, Journal Year: 2023, Volume and Issue: 28(7), P. 3166 - 3166

Published: April 2, 2023

In this work, we describe the synthesis of new macrocycles derived from 3-phenyl-1,2,4-triazole-5-thione 1 in a heterogeneous medium using liquid-solid phase transfer catalysis (PTC) conditions. The structures two compounds (3 and 4) isolated were elucidated based on spectral data (1H-NMR, 13C-NMR) confirmed case 3-phenyl-1,2,4-triazolo [3,4-h]-13,4--thiaza-11-crown-4 (3) by single-crystal X-ray diffraction analysis. Furthermore, experimental geometrical parameters compared with their corresponding predicted ones obtained at B3LYP/6-311++G(d,p) level theory. intercontacts between crystal units investigated through Hirshfeld surface drug-like ADMET drug-likeness properties, which showed that 3 may act as an inhibitor DNA-dependent protein kinase (DNA-PK). This assumption was well-binding fitting into binding site DNA-PK formation stable 3-DNA-PK complex energy -7 kcal-mol-1. Finally, anticancer activity assessed MTT assay against A549 cells, has moderate to doxorubicin reference drug.

Language: Английский

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Strategies for Conditional Regulation of Proteins

JACS Au, Journal Year: 2023, Volume and Issue: 3(2), P. 344 - 357

Published: Jan. 26, 2023

Design of the next-generation therapeutics, biosensors, and molecular tools for basic research requires that we bring protein activity under control. Each has unique properties, therefore, it is critical to tailor current techniques develop new regulatory methods regulate proteins interest (POIs). This perspective gives an overview widely used stimuli synthetic natural conditional regulation proteins.

Language: Английский

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