ATM Kinase-Dependent Regulation of Autophagy: A Key Player in Senescence?

Stagni, Venturina; Ferri, Alessandra; Cirotti, Claudia; Barilá, Daniela

doi:10.3389/fcell.2020.599048

Cited by 34 publications

(30 citation statements)

References 64 publications

(89 reference statements)

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“…Its reversal by AP20187 treatment suggests that cells expressing the INK-ATTAC cassette and eliminated by the AP20187 treatment are the major responders to the oxidative damage and associated DNA damage. DNA damage is known to induce cellular senescence via cyclin dependent kinase inhibitor genes ( Fischer and Muller, 2017 ; Stagni et al, 2021 ). Indeed Cdkn2B (p15 Ink4b ; Ref.…”

Section: Resultsmentioning

confidence: 99%

Low Dose Chronic Angiotensin II Induces Selective Senescence of Kidney Endothelial Cells

Khan

Schmidt

Kallakury

et al. 2021

Front. Cell Dev. Biol.

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Angiotensin II can cause oxidative stress and increased blood pressure that result in long term cardiovascular pathologies. Here we evaluated the contribution of cellular senescence to the effect of chronic exposure to low dose angiotensin II in a model that mimics long term tissue damage. We utilized the INK-ATTAC (p16Ink4a–Apoptosis Through Targeted Activation of Caspase 8) transgenic mouse model that allows for conditional elimination of p16Ink4a -dependent senescent cells by administration of AP20187. Angiotensin II treatment for 3 weeks induced ATTAC transgene expression in kidneys but not in lung, spleen and brain tissues. In the kidneys increased expression of ATM, p15 and p21 matched with angiotensin II induction of senescence-associated secretory phenotype genes MMP3, FGF2, IGFBP2, and tPA. Senescent cells in the kidneys were identified as endothelial cells by detection of GFP expressed from the ATTAC transgene and increased expression of angiopoietin 2 and von Willebrand Factor, indicative of endothelial cell damage. Furthermore, angiotensin II induced expression of the inflammation-related glycoprotein versican and immune cell recruitment to the kidneys. AP20187-mediated elimination of p16-dependent senescent cells prevented physiologic, cellular and molecular responses to angiotensin II and provides mechanistic evidence of cellular senescence as a driver of angiotensin II effects.

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Section: Resultsmentioning

confidence: 99%

Low Dose Chronic Angiotensin II Induces Selective Senescence of Kidney Endothelial Cells

Khan

Schmidt

Kallakury

et al. 2021

Front. Cell Dev. Biol.

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“…Since damaged such organelles need to be removed, autophagy machinery is activated. Many factors cause damage to organelles, and in the case of damage by DNA damaging agents, studies are continuing to show that autophagy is activated to control cell fate to maintain homeostasis in cells (Stagni et al, 2020). ATM, the major sensor of DSB, is involved in generating signal transduction by recognizing the damaged area when DNA damage occurs, and autophagy is activated by this ATM pathway (Eliopoulos et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Autophagic Organelles in DNA Damage Response

Kim

Lee

Kim

et al. 2021

Front. Cell Dev. Biol.

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Autophagy is an important subcellular event engaged in the maintenance of cellular homeostasis via the degradation of cargo proteins and malfunctioning organelles. In response to cellular stresses, like nutrient deprivation, infection, and DNA damaging agents, autophagy is activated to reduce the damage and restore cellular homeostasis. One of the responses to cellular stresses is the DNA damage response (DDR), the intracellular pathway that senses and repairs damaged DNA. Proper regulation of these pathways is crucial for preventing diseases. The involvement of autophagy in the repair and elimination of DNA aberrations is essential for cell survival and recovery to normal conditions, highlighting the importance of autophagy in the resolution of cell fate. In this review, we summarized the latest information about autophagic recycling of mitochondria, endoplasmic reticulum (ER), and ribosomes (called mitophagy, ER-phagy, and ribophagy, respectively) in response to DNA damage. In addition, we have described the key events necessary for a comprehensive understanding of autophagy signaling networks. Finally, we have highlighted the importance of the autophagy activated by DDR and appropriate regulation of autophagic organelles, suggesting insights for future studies. Especially, DDR from DNA damaging agents including ionizing radiation (IR) or anti-cancer drugs, induces damage to subcellular organelles and autophagy is the key mechanism for removing impaired organelles.

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“…In lymphopenic patients a decline of both CD4 + and CD19 + cells was noted, but classical opportunistic infections, as that from Pneumocystis jirovecii, did not occur in our cohort of AT patients, indicating that the quantitative deterioration of these cells does not equate a functional progressive immune deficiency. It has been reported that the loss of ATM expression in AT cells triggers a senescent-like phenotype, including upregulation of genes associated to senescence and cancer, decreased cellular replication capacity, shortening telomeres, and autophagy abnormalities [32][33][34][35]. The progressive immunological deterioration in AT patients, which parallels the neurological impairment, may account for the increased frequency or greater severity of infections with age.…”

Section: Discussionmentioning

confidence: 99%

Progressive Depletion of B and T Lymphocytes in Patients with Ataxia Telangiectasia: Results of the Italian Primary Immunodeficiency Network

Cirillo¹,

Polizzi

Soresina

et al. 2022

J Clin Immunol

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Ataxia telangiectasia (AT) is a rare neurodegenerative genetic disorder due to bi-allelic mutations in the Ataxia Telangiectasia Mutated (ATM) gene. The aim of this paper is to better define the immunological profile over time, the clinical immune-related manifestations at diagnosis and during follow-up, and to attempt a genotype–phenotype correlation of an Italian cohort of AT patients. Retrospective data of 69 AT patients diagnosed between December 1984 and November 2019 were collected from the database of the Italian Primary Immunodeficiency Network. Patients were classified at diagnosis as lymphopenic (Group A) or non-lymphopenic (Group B). Fifty eight out of 69 AT patients (84%) were genetically characterized and distinguished according to the type of mutations in truncating/truncating (TT; 27 patients), non-truncating (NT)/T (28 patients), and NT/NT (5 patients). In 3 patients, only one mutation was detected. Data on age at onset and at diagnosis, cellular and humoral compartment at diagnosis and follow-up, infectious diseases, signs of immune dysregulation, cancer, and survival were analyzed and compared to the genotype. Lymphopenia at diagnosis was related per se to earlier age at onset. Progressive reduction of cellular compartment occurred during the follow-up with a gradual reduction of T and B cell number. Most patients of Group A carried bi-allelic truncating mutations, had a more severe B cell lymphopenia, and a reduced life expectancy. A trend to higher frequency of interstitial lung disease, immune dysregulation, and malignancy was noted in Group B patients. Lymphopenia at the onset and the T/T genotype are associated with a worst clinical course. Several mechanisms may underlie the premature and progressive immune decline in AT subjects.

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ATM Kinase-Dependent Regulation of Autophagy: A Key Player in Senescence?

Cited by 34 publications

References 64 publications

Low Dose Chronic Angiotensin II Induces Selective Senescence of Kidney Endothelial Cells

Low Dose Chronic Angiotensin II Induces Selective Senescence of Kidney Endothelial Cells

Autophagic Organelles in DNA Damage Response

Progressive Depletion of B and T Lymphocytes in Patients with Ataxia Telangiectasia: Results of the Italian Primary Immunodeficiency Network

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