Regulation of transcription patterns, poly-ADP-ribose, and RNA-DNA hybrids by the ATM protein kinase DOI Creative Commons
Phillip R. Woolley, Xuemei Wen, Olivia M. Conway

et al.

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

Published: Dec. 7, 2023

The ATM protein kinase is a master regulator of the DNA damage response and also an important sensor oxidative stress. Analysis gene expression in Ataxia-telangiectasia patient brain tissue shows that large-scale transcriptional changes occur cerebellum correlate with level GC content transcribed genes. In human neuron-like cells culture we map locations poly-ADP-ribose RNA-DNA hybrid accumulation genome-wide inhibition find these marks coincide high transcription levels, active histone marks, content. Antioxidant treatment reverses R-loops regions, consistent central role ROS promoting lesions. Based on results postulate transcription-associated lesions accumulate ATM-deficient single-strand breaks PARylation at sites ultimately generate compromise function lead to neurodegeneration over time A-T patients.

Language: Английский

Redox regulation: mechanisms, biology and therapeutic targets in diseases DOI Creative Commons
Bowen Li, Hui Ming, Siyuan Qin

et al.

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

Citations

4
Oxidative stress and the multifaceted roles of ATM in maintaining cellular redox homeostasis DOI Creative Commons
Ji‐Hoon Lee

Redox Biology, Journal Year: 2024, Volume and Issue: 75, P. 103269 - 103269

Published: July 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.

Language: Английский

Citations

9
A-T neurodegeneration and DNA damage-induced transcriptional stress DOI
Tanya T. Paull, Phillip R. Woolley

DNA repair, Journal Year: 2024, Volume and Issue: 135, P. 103647 - 103647

Published: Feb. 15, 2024

Language: Английский

Citations

7
Structural Motifs at the Telomeres and Their Role in Regulatory Pathways DOI Creative Commons

Abeer F. R. Alanazi,

Gary N. Parkinson, Shozeb Haider

et al.

Biochemistry, Journal Year: 2024, Volume and Issue: 63(7), P. 827 - 842

Published: March 14, 2024

Telomeres are specialized structures, found at the ends of linear chromosomes in eukaryotic cells, that play a crucial role maintaining stability and integrity genomes. They composed repetitive DNA sequences, ssDNA overhangs, several associated proteins. The length telomeres is linked to cellular aging humans, deficiencies their maintenance with various diseases. Key structural motifs serve protect vulnerable chromosomal ends. Telomeric also has ability form diverse complex higher-order including T-loops, D-loops, R-loops, G-loops, G-quadruplexes, i-motifs, complementary C-rich strand. While many essential proteins have been identified, intricacies interactions details still not fully understood. This Perspective highlights recent advancements comprehending structures human telomeres. It emphasizes significance telomeres, explores telomeric motifs, delves into biology surrounding telomerase. Furthermore, loops, topologies, contribute safeguarding discussed.

Language: Английский

Citations

7
Regulation of transcription patterns, poly(ADP-ribose), and RNA-DNA hybrids by the ATM protein kinase DOI Creative Commons
Phillip R. Woolley, Xuemei Wen, Olivia M. Conway

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(3), P. 113896 - 113896

Published: March 1, 2024

The ataxia telangiectasia mutated (ATM) protein kinase is a master regulator of the DNA damage response and also an important sensor oxidative stress. Analysis gene expression in ataxia-telangiectasia (A-T) patient brain tissue shows that large-scale transcriptional changes occur cerebellum correlate with level guanine-cytosine (GC) content transcribed genes. In human neuron-like cells culture, we map locations poly(ADP-ribose) RNA-DNA hybrid accumulation genome-wide ATM inhibition find these marks coincide high transcription levels, active histone marks, GC content. Antioxidant treatment reverses R-loops regions, consistent central role reactive oxygen species promoting lesions. Based on results, postulate transcription-associated lesions accumulate ATM-deficient single-strand breaks PARylation at sites ultimately generate compromise function lead to neurodegeneration over time A-T patients.

Language: Английский

Citations

4
Insights into Calpain Activation and Rho-ROCK Signaling in Parkinson’s Disease and Aging DOI Creative Commons

Amy Gathings,

Vandana Zaman,

Narendra L. Banik

et al.

Biomedicines, Journal Year: 2024, Volume and Issue: 12(5), P. 1074 - 1074

Published: May 13, 2024

Parkinson’s disease (PD), a progressive neurodegenerative disease, has no cure, and current therapies are not effective at halting progression. The affects mid-brain dopaminergic neurons and, subsequently, the spinal cord, contributing to many debilitating symptoms associated with PD. GTP-binding protein, Rho, plays significant role in cellular pathology of downstream effector Rho-associated kinase (ROCK), multiple functions, including microglial activation induction inflammatory responses. Activated microglia have been implicated diseases, PD, that initiate responses, leading neuron death. Calpain expression activity is increased following glial activation, which triggers Rho-ROCK pathway induces T cell migration as well mediates toxic α-synuclein (α-syn) aggregation death, indicating pivotal for calpain degenerative processes Increased may represent new mechanism oxidative damage aging. This review will summarize stress α-syn aggregation, their influence on process PD aging, possible strategies research directions therapeutic intervention.

Language: Английский

Citations

4
Radiation symptoms resemble laminopathies and the physical underlying cause may sit at the lamin A C-terminus DOI Creative Commons

A Waldherr,

Anna Fogtman

Molecular Medicine, Journal Year: 2025, Volume and Issue: 31(1)

Published: Feb. 20, 2025

Ionizing radiation causes three divergent effects in the human body: On one side, tissue death (= deterministic effects) sets on, on other mutations and cancer growth stochastic can occur. In recent years, additional phenomenon of accelerated aging has come to light. following, we argue that these seemingly contradictory responses namely: (i) increased growth, (ii) ablation or (iii) senescence, share an underlying cause from damage at lamin A C-terminus. words, besides typically described genomic impact, propose destabilization pathway via oxidation nuclear envelope. We five concrete hypotheses draw a direct mechanistic model cellular oxidative stress, micronuclei clinical symptoms. conjunction with B compensation, might be able explain why dominate. If our holds true, novel target for radiotherapeutics radiooncology arises, rationale closer connect laminopathy radioprotection research.

Language: Английский

Citations

0
Profiling Tel1 Signaling Reveals a Non-Canonical Motif Targeting DNA Repair and Telomere Control Machineries DOI Creative Commons
William Comstock, Shrijan Bhattarai, Ethan J. Sanford

et al.

Journal of Biological Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108194 - 108194

Published: Jan. 1, 2025

Language: Английский

Citations

0
Asymmetric activation of dimeric ATM/Tel1 kinase DOI Creative Commons
P WANG,

Zexuan Zheng,

Guangxian Wang

et al.

Cell Discovery, Journal Year: 2025, Volume and Issue: 11(1)

Published: March 25, 2025

Language: Английский

Citations

0
Replicative senescence is ATM driven, reversible, and accelerated by hyperactivation of ATM at normoxia DOI Creative Commons
Alexander Stuart, Titia de Lange

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 26, 2024

Programmed telomere shortening limits tumorigenesis through the induction of replicative senescence. Here we address three long-standing questions concerning First, show that ATM kinase is solely responsible for Senescence was delayed by inhibition (ATMi) or overexpression TRF2, shelterin subunit dedicated to repression. In contrast, there no evidence ATR signaling contributing senescence even when ATMi combined with inhibition. Second, can induce apparently normal cell divisions in a subset senescent cells, indicating be reversed. Third, extended life span at low (physiological) oxygen due diminished activity. At oxygen, cells decreased response dysfunctional telomeres and genome-wide DSBs compared 20% oxygen. As this effect could reversed NAC, attenuated critically short resulting likely ROS-induced formation cysteine disulfide-bridges crosslink dimers into form not activated DSBs. These findings how primary human detect shortened reveal molecular mechanism underlying tumor suppressor pathway.

Language: Английский

Citations

2