DNA repair, Год журнала: 2024, Номер 145, С. 103788 - 103788
Опубликована: Ноя. 14, 2024
Язык: Английский
Redox Biology, Год журнала: 2024, Номер 75, С. 103269 - 103269
Опубликована: Июль 16, 2024
The ataxia telangiectasia mutated (ATM) protein kinase is best known as a master regulator of the DNA damage response. However, accumulating evidence has unveiled an equally vital function for ATM in sensing oxidative stress and orchestrating cellular antioxidant defenses to maintain redox homeostasis. can be activated through non-canonical pathway involving intermolecular disulfide crosslinking dimers, distinct from its canonical activation by double-strand breaks. Structural studies have elucidated conformational changes that allow switch into active redox-sensing state upon oxidation. Notably, loss results elevated reactive oxygen species (ROS) levels, altered profiles, mitochondrial dysfunction across multiple cell types tissues. This arising deficiency been implicated central driver neurodegenerative phenotypes ataxia-telangiectasia (A-T) patients, potentially mechanisms damage, PARP hyperactivation, widespread aggregation. Moreover, defective oxidation disrupts transcriptional programs RNA metabolism, with detrimental impacts on neuronal Significantly, therapy ameliorate organismal abnormalities various ATM-deficient models. review synthesizes recent advances illuminating multifaceted roles preserving balance mitigating insults, providing unifying paradigm understanding complex pathogenesis A-T disease.
Язык: Английский
Процитировано
6
MedComm, Год журнала: 2024, Номер 5(11)
Опубликована: Окт. 31, 2024
DNA damage response (DDR) pathway is the coordinated cellular network dealing with identification, signaling, and repair of damage. It tightly regulates cell cycle progression promotes to minimize daughter cells. Key proteins involved in DDR are frequently mutated/inactivated human cancers promote genomic instability, a recognized hallmark cancer. Besides being an intrinsic property tumors, also represents unique therapeutic opportunity. Indeed, inhibition expected delay repair, causing persistent unrepaired breaks, interfere progression, sensitize cancer cells several DNA-damaging agents, such as radiotherapy chemotherapy. In addition, defects have been shown render these more dependent on remaining pathways, which could be targeted very specifically (synthetic lethal approach). Research over past two decades has led synthesis testing hundreds small inhibitors against key proteins, some antitumor activity cancers. parallel, search for synthetic lethality interaction broadening use inhibitors. this review, we discuss state-of-art ataxia-telangiectasia mutated, ataxia-telangiectasia-and-Rad3-related protein, checkpoint kinase 1, Wee1 Polθ inhibitors, highlighting results obtained ongoing clinical trials both monotherapy combination chemotherapy radiotherapy.
Язык: Английский
Процитировано
4
Elsevier eBooks, Год журнала: 2025, Номер unknown, С. 123 - 175
Опубликована: Янв. 1, 2025
Язык: Английский
Процитировано
0
Muscle & Nerve, Год журнала: 2025, Номер unknown
Опубликована: Март 14, 2025
ABSTRACT Introduction/Aims Ataxia‐telangiectasia (A‐T) is a genetic multisystem neurodegenerative disorder characterized by cerebellar ataxia, oculocutaneous telangiectasia, extrapyramidal involvement, peripheral sensorimotor neuropathy, immunodeficiency, pulmonary disease, and an increased risk of malignancy that ultimately determines the shortened lifespan in many patients. A‐T nerve ultrasonographic characteristics remain underexplored. This pilot study aimed to characterize morphology nerves patients with A‐T. Methods Ultrasound cross‐sectional areas (CSAs) median, ulnar, sural, tibial were obtained from three compared reference values. Nerve conduction studies electromyography also performed. Given small sample size exploratory nature this study, formal statistical analyses not performed, descriptive statistics presented for data. Results CSAs smaller than healthy controls at all measurement sites. Discussion ultrasound revealed atrophy reduction may distinguish highlights utility as non‐invasive diagnostic tool neuropathy. These findings have important implications early detection clinical practice.
Язык: Английский
Процитировано
0
Ageing Research Reviews, Год журнала: 2024, Номер unknown, С. 102519 - 102519
Опубликована: Сен. 1, 2024
Язык: Английский
Процитировано
3
Neurobiology of Disease, Год журнала: 2024, Номер 202, С. 106710 - 106710
Опубликована: Окт. 28, 2024
Neurodegenerative diseases (NDs) are a type of common chronic progressive disorders characterized by damage to specific cell populations in the nervous system, ultimately leading disability or death. Effective treatments for these still lacking, due limited understanding their pathogeneses, which involve multiple cellular and molecular pathways. The triggering an immune response is feature neurodegenerative disorders. A critical challenge intricate interplay between neuroinflammation, neurodegeneration, responses, not yet fully characterized. In recent years, cyclic GMP-AMP synthase (cGAS)-stimulator interferon gene (STING) pathway, crucial intracellular DNA sensing, has gradually gained attention. However, roles this pathway within types such as cells, glial neuronal its contribution ND pathogenesis, remain elucidated. review, we systematically explore how cGAS-STING signaling links various with related effector pathways under context NDs multifaceted therapeutic directions. We emphasize discovery condition-dependent heterogeneity integral diverse responses potential targets. Additionally, review pathogenic role activation Parkinson's disease, ataxia-telangiectasia, amyotrophic lateral sclerosis. focus on complex bidirectional Alzheimer's Huntington's sclerosis, revealing double-edged nature disease progression. objective elucidate pivotal pathogenesis catalyze new insights facilitating development novel strategies.
Язык: Английский
Процитировано
3
DNA repair, Год журнала: 2024, Номер 145, С. 103788 - 103788
Опубликована: Ноя. 14, 2024
Язык: Английский
Процитировано
0