scholarly journals Ataxia Telangiectasia Mutated Protein Kinase: A Potential Master Puppeteer of Oxidative Stress-Induced Metabolic Recycling

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Marguerite Blignaut ◽  
Sarah Harries ◽  
Amanda Lochner ◽  
Barbara Huisamen
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Protein Kinase ◽  
Ataxia Telangiectasia ◽  
Regulatory Protein ◽  
Protein Aggregates ◽  
Ataxia Telangiectasia Mutated ◽  
Damage Repair ◽  
Ataxia Telangiectasia Mutated Protein

Ataxia Telangiectasia Mutated protein kinase (ATM) has recently come to the fore as a regulatory protein fulfilling many roles in the fine balancing act of metabolic homeostasis. Best known for its role as a transducer of DNA damage repair, the activity of ATM in the cytosol is enjoying increasing attention, where it plays a central role in general cellular recycling (macroautophagy) as well as the targeted clearance (selective autophagy) of damaged mitochondria and peroxisomes in response to oxidative stress, independently of the DNA damage response. The importance of ATM activation by oxidative stress has also recently been highlighted in the clearance of protein aggregates, where the expression of a functional ATM construct that cannot be activated by oxidative stress resulted in widespread accumulation of protein aggregates. This review will discuss the role of ATM in general autophagy, mitophagy, and pexophagy as well as aggrephagy and crosstalk between oxidative stress as an activator of ATM and its potential role as a master regulator of these processes.

scholarly journals SIRT7-mediated ATM deacetylation is essential for its deactivation and DNA damage repair

2019 ◽  
Vol 5 (3) ◽  
pp. eaav1118 ◽  
Author(s):  
Ming Tang ◽  
Zhiming Li ◽  
Chaohua Zhang ◽  
Xiaopeng Lu ◽  
Bo Tu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Class Iii ◽  
Ataxia Telangiectasia Mutated ◽  
Damage Repair ◽  
Damage Response ◽  
Late Stages

The activation of ataxia-telangiectasia mutated (ATM) upon DNA damage involves a cascade of reactions, including acetylation by TIP60 and autophosphorylation. However, how ATM is progressively deactivated after completing DNA damage repair remains obscure. Here, we report that sirtuin 7 (SIRT7)–mediated deacetylation is essential for dephosphorylation and deactivation of ATM. We show that SIRT7, a class III histone deacetylase, interacts with and deacetylates ATM in vitro and in vivo. In response to DNA damage, SIRT7 is mobilized onto chromatin and deacetylates ATM during the late stages of DNA damage response, when ATM is being gradually deactivated. Deacetylation of ATM by SIRT7 is prerequisite for its dephosphorylation by its phosphatase WIP1. Consequently, depletion of SIRT7 or acetylation-mimic mutation of ATM induces persistent ATM phosphorylation and activation, thus leading to impaired DNA damage repair. Together, our findings reveal a previously unidentified role of SIRT7 in regulating ATM activity and DNA damage repair.

Activation of and dependence on ataxia telangiectasia mutated kinase in PTEN-deficient tumor cells.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10553-10553
Author(s):  
Nuala McCabe ◽  
Steven M. Walker ◽  
Nicolas Goffard ◽  
Katarina Wikstrom ◽  
Caroline Greenan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Oxidative Stress ◽  
Ovarian Cancer ◽  
Dna Damage ◽  
Ataxia Telangiectasia ◽  
Clustering Analysis ◽  
Gene List ◽  
Hierarchical Clustering Analysis ◽  
Wild Type ◽  
Ataxia Telangiectasia Mutated

10553 Background: Loss of PTEN function has been widely reported to cause up-regulation of the PI3K/AKT signalling pathway resulting in increased cell growth, proliferation and survival. More recently it has been reported that PTEN null cells demonstrate genomic instability and have increased production of reactive oxygen species (ROS) and oxidative stress induced DNA damage. Ataxia Telangiectasia Mutated (ATM) is the primary response kinase, which responds to stalled DNA replication and DNA double strand breaks due to oxidative DNA damage. Methods: A metagene representing ATM activation was generated from cell line data and used to perform hierarchical clustering analysis of public DNA microarray profiling datasets of breast cancer, ovarian cancer and glioblastoma with known PTEN IHC/mutation status. Furthermore, we ask if ATM activation may be therapeutically exploited in PTEN null tumours using ATM specific siRNA and compounds in 2 PTEN isogenic cell line model systems. Results: We show that PTEN null cells have elevated levels of ROS, DNA damage and have endogenous activation of ATM, an enzyme important in responding to DNA damage resulting from oxidative stress. We hypothesised that PTEN deficient tumours may rely on ATM enzyme for survival. To investigate this we generated a 189-gene list representing ATM activation and used this to perform hierarchical clustering analysis of a breast cancer DNA microarray dataset. This list was able to significantly cluster tumours with known loss of PTEN expression (p=0.004). Furthermore, this gene list was able to segregate PTEN null/mutant tumours from PTEN wild-type tumours in 2 independent datasets of glioblastoma and ovarian cancer (p=0.015 and p=0.012). In addition, we found that inhibition of ATM using the selective inhibitor KU-55933 caused DNA damage, cell cycle arrest and apoptosis specifically in PTEN deficient cells when compared to PTEN wild-type cells. Conclusions: These observations suggest that ATM may represent a therapeutic target in PTEN deficient tumours and furthermore ATM activation may be the basis of a biomarker of PTEN status in human cancers.

Role of Oxidative Stress and DNA Damage/Repair in Lung Cancer

2021 ◽  
pp. 1-21
Author(s):  
Joytri Dutta ◽  
Sabita Singh ◽  
Ashish Jaiswal ◽  
Archita Ray ◽  
Pamelika Das ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lung Cancer ◽  
Dna Damage ◽  
Dna Damage Repair ◽  
Damage Repair

scholarly journals MicroRNA-18a Attenuates DNA Damage Repair through Suppressing the Expression of Ataxia Telangiectasia Mutated in Colorectal Cancer

PLoS ONE ◽  
2013 ◽  
Vol 8 (2) ◽  
pp. e57036 ◽  
Author(s):  
Chung-Wah Wu ◽  
Yu-Juan Dong ◽  
Qiao-Yi Liang ◽  
Xin-Qi He ◽  
Simon S. M. Ng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Ataxia Telangiectasia ◽  
Dna Damage Repair ◽  
Ataxia Telangiectasia Mutated ◽  
Damage Repair

scholarly journals Ataxia-telangiectasia Mutated Kinase (ATM) as a Central Regulator of Radiation-induced DNA Damage Response

2010 ◽  
Vol 53 (1) ◽  
pp. 13-17 ◽  
Author(s):  
Aleš Tichý ◽  
Jiřina Vávrová ◽  
Jaroslav Pejchal ◽  
Martina Řezáčová
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Protein Kinase ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
Ataxia Telangiectasia Mutated ◽  
Damage Response ◽  
Radiation Induced ◽  
Inducible Protein

Ataxia-telangiectasia mutated kinase (ATM) is a DNA damage-inducible protein kinase, which phosphorylates plethora of substrates participating in DNA damage response. ATM significance for the cell faith is undeniable, since it regulates DNA repair, cell-cycle progress, and apoptosis. Here we describe its main signalling targets and discuss its importance in DNA repair as well as novel findings linked to this key regulatory enzyme in the terms of ionizing radiationinduced DNA damage.

scholarly journals Ataxia Telangiectasia-mutated Protein Can Regulate p53 and Neuronal Death Independent of Chk2 in Response to DNA Damage

2003 ◽  
Vol 278 (39) ◽  
pp. 37782-37789 ◽  
Author(s):  
Elizabeth Keramaris ◽  
Atsushi Hirao ◽  
Ruth S. Slack ◽  
Tak W. Mak ◽  
David S. Park
Keyword(s):  
Dna Damage ◽  
Neuronal Death ◽  
Ataxia Telangiectasia ◽  
Ataxia Telangiectasia Mutated ◽  
Ataxia Telangiectasia Mutated Protein
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