A multifaceted role for ATM in genome maintenance

2003 ◽  
Vol 5 (16) ◽  
pp. 1-21 ◽  
Author(s):  
Tej K. Pandita
Keyword(s):  
Cell Cycle ◽  
Ataxia Telangiectasia ◽  
Cell Cycle Control ◽  
Cell Cycle Checkpoints ◽  
Telomere Maintenance ◽  
Loss Of Function ◽  
Genome Maintenance ◽  
Ataxia Telangiectasia Mutated ◽  
Gonadal Atrophy ◽  
Mitogenic Signal Transduction

The pleiotropic nature of the clinical phenotypes of patients with ataxia-telangiectasia (A-T) – which encompass cerebellar degeneration (leading to ataxia), gonadal atrophy, and cancer predisposition – suggests multiple functions of the gene responsible for the disease. The ataxia-telangiectasia mutated gene product (ATM), whose loss of function is responsible for ataxia-telangiectasia, is a protein kinase that interacts with several substrates and is implicated in mitogenic signal transduction, chromosome condensation, meiotic recombination, cell-cycle control and telomere maintenance. This review focuses on the critical roles that ATM appears to play in cell-cycle checkpoints, DNA repair, telomere metabolism and oxidative stress, indicating how defects in these processes might lead to ataxia-telangiectasia.

scholarly journals Effect of ATR Inhibition in RT Response of HPV-Negative and HPV-Positive Head and Neck Cancers

2021 ◽  
Vol 22 (4) ◽  
pp. 1504
Author(s):  
Rüveyda Dok ◽  
Mary Glorieux ◽  
Marieke Bamps ◽  
Sandra Nuyts
Keyword(s):  
Head And Neck ◽  
Ataxia Telangiectasia ◽  
Cell Cycle Checkpoints ◽  
Specific Cell ◽  
Ataxia Telangiectasia Mutated ◽  
Checkpoint Kinase 1 ◽  
Hpv Status ◽  
Damage Response ◽  
Xenograft Models ◽  
Potential Use

Radiotherapy (RT) has a central role in head and neck squamous cell carcinoma (HNSCC) treatment. Targeted therapies modulating DNA damage response (DDR) and more specific cell cycle checkpoints can improve the radiotherapeutic response. Here, we assessed the influence of ataxia-telangiectasia mutated and Rad3-related (ATR) inhibition with the ATR inhibitor AZD6738 on RT response in both human papillomavirus (HPV)-negative and HPV-positive HNSCC. We found that ATR inhibition enhanced RT response in HPV-negative and HPV-positive cell lines independent of HPV status. The radiosensitizing effect of AZD6738 was correlated with checkpoint kinase 1 (CHK1)-mediated abrogation of G2/M-arrest. This resulted in the inhibition of RT-induced DNA repair and in an increase in the percentage of micronucleated cells. We validated the enhanced RT response in HPV-negative and HPV-positive xenograft models. These data demonstrate the potential use of ATR inhibition in combination with RT as a treatment option for both HPV-negative and HPV-positive HNSCC patients.

scholarly journals The transcription factors TFE3 and TFEB amplify p53 dependent transcriptional programs in response to DNA damage

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Eutteum Jeong ◽  
Owen A Brady ◽  
José A Martina ◽  
Mehdi Pirooznia ◽  
Ilker Tunc ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Transcription Factors ◽  
P53 Protein ◽  
Cell Cycle Control ◽  
Cell Cycle Checkpoints ◽  
Dependent Manner ◽  
Double Knockout ◽  
Protein Levels ◽  
Regulation Of Cell Cycle

The transcription factors TFE3 and TFEB cooperate to regulate autophagy induction and lysosome biogenesis in response to starvation. Here we demonstrate that DNA damage activates TFE3 and TFEB in a p53 and mTORC1 dependent manner. RNA-Seq analysis of TFEB/TFE3 double-knockout cells exposed to etoposide reveals a profound dysregulation of the DNA damage response, including upstream regulators and downstream p53 targets. TFE3 and TFEB contribute to sustain p53-dependent response by stabilizing p53 protein levels. In TFEB/TFE3 DKOs, p53 half-life is significantly decreased due to elevated Mdm2 levels. Transcriptional profiles of genes involved in lysosome membrane permeabilization and cell death pathways are dysregulated in TFEB/TFE3-depleted cells. Consequently, prolonged DNA damage results in impaired LMP and apoptosis induction. Finally, expression of multiple genes implicated in cell cycle control is altered in TFEB/TFE3 DKOs, revealing a previously unrecognized role of TFEB and TFE3 in the regulation of cell cycle checkpoints in response to stress.

scholarly journals SAT-LB57 The Spectrum of Genomic and Transcriptomic Alterations in ACTH-Producing and ACTH-Silent Corticotroph Adenomas

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Antonio Marcondes Lerario ◽  
David Meredith ◽  
Joseph Castlen ◽  
Lauren M Johnson ◽  
Michael Catalino ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Chromosomal Instability ◽  
Chromosomal Abnormalities ◽  
Dominant Role ◽  
Telomere Maintenance ◽  
High Morbidity ◽  
Disease Course ◽  
Loss Of Function ◽  
Aggressive Disease ◽  
Corticotroph Adenomas

Abstract Corticotroph adenomas (CA) are rare pituitary tumors that impose several challenges in clinical management - CA are difficult to diagnose, often recur, and are associated with high morbidity and mortality. CA are characteristically Tpit-positive and PIT1-negative and comprise ACTH-producing (Cushing’s disease (CD)) and ACTH-silent (AS) classes. The molecular programs contributing to disease pathogenesis in CA are still poorly characterized, largely restricted to the identification of somatic mutations in USP8 in 40-60% of CD adenomas. To more fully characterize the mutational and transcriptional landscape driving both classes of CA, we performed whole-exome sequencing and RNA-seq in 19 CD and 16 AS adenomas. We identified USP8 mutations in 53% of CD (10/19) and 6% of AS (1/16) samples. Strikingly, in 19% of AS tumors (3/16), all exhibiting an unusually aggressive disease course, including two cases with brain metastases, we identified recurrent somatic pathogenic mutations in TP53 and novel loss-of-function mutations in telomere maintenance genes DAXX and ATRX. Furthermore, while all tumors with USP8 mutations (regardless of CD/AS status) exhibited no chromosomal abnormalities as measured by copy-number variation (CNV) and loss of heterozygosity (LOH) analysis, 33% of CD (4/12, including 1 tumor with a DAXX mutation) and 36% of AS (4/11, including all DAXX/ATRX-mutated cases) samples exhibited profound chromosomal instability, characterized by hyperdiploidy, widespread whole-chromosome LOH events, and arm-level breakpoints. Using transcriptome analysis (n=22), we identified three classes of tumors (C1-C3), reflecting these distinct somatic alteration profiles. C1 tumors (n=6) are characterized by chromosomal stability, includes exclusively USP8-mutated CD, and exhibits upregulation of genes involved in metabolic processes and protein acetylation. C2 tumors (n=10) are comprised exclusively of AS (including all TP53- and/or DAXX/ATRX-mutated cases), are characterized by chromosomal instability, and exhibits concordant upregulation of cell cycle programs. Finally, C3 (n=6) contains a mixture of AS and CD cases (including CD without mutations in USP8) and features an expression profile that partly overlap with C1 tumors, but also exhibit higher expression of inflammatory genes. Taken together, our data suggest that CD and AS are distinct molecular subtypes of CA, highlighting the dominant role of USP8 mutations in driving a unique transcriptional program and illustrate for the first time that unlike most cases of CD, AS cases are characterized by profound genomic instability and cell cycle activation, features associated with a more aggressive disease course.

ATR (ataxia telangiectasia mutated- and Rad3-related kinase) is activated by mild hypothermia in mammalian cells and subsequently activates p53

2011 ◽  
Vol 435 (2) ◽  
pp. 499-508 ◽  
Author(s):  
Anne Roobol ◽  
Jo Roobol ◽  
Martin J. Carden ◽  
Amandine Bastide ◽  
Anne E. Willis ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ataxia Telangiectasia ◽  
Mammalian Cells ◽  
Mild Hypothermia ◽  
Chinese Hamster ◽  
Membrane Lipid ◽  
Mitogen Activated Protein Kinase ◽  
Ataxia Telangiectasia Mutated ◽  
Mitogen Activated Protein

In vitro cultured mammalian cells respond to mild hypothermia (27–33 °C) by attenuating cellular processes and slowing and arresting the cell cycle. The slowing of the cell cycle at the upper range (31–33 °C) and its complete arrest at the lower range (27–28 °C) of mild hypothermia is effected by the activation of p53 and subsequent expression of p21. However, the mechanism by which cold is perceived in mammalian cells with the subsequent activation of p53 has remained undetermined. In the present paper, we report that the exposure of Chinese-hamster ovary-K1 cells to mildly hypothermic conditions activates the ATR (ataxia telangiectasia mutated- and Rad3-related kinase)–p53–p21 signalling pathway and is thus a key pathway involved in p53 activation upon mild hypothermia. In addition, we show that although p38MAPK (p38 mitogen-activated protein kinase) is also involved in activation of p53 upon mild hypothermia, this is probably the result of activation of p38MAPK by ATR. Furthermore, we show that cold-induced changes in cell membrane lipid composition are correlated with the activation of the ATR–p53–p21 pathway. Therefore we provide the first mechanistic detail of cell sensing and signalling upon mild hypothermia in mammalian cells leading to p53 and p21 activation, which is known to lead to cell cycle arrest.

scholarly journals Chk2 Is a Tumor Suppressor That Regulates Apoptosis in both an Ataxia Telangiectasia Mutated (ATM)-Dependent and an ATM-Independent Manner

2002 ◽  
Vol 22 (18) ◽  
pp. 6521-6532 ◽  
Author(s):  
Atsushi Hirao ◽  
Alison Cheung ◽  
Gordon Duncan ◽  
Pierre-Marie Girard ◽  
Andrew J. Elia ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Cell Cycle Arrest ◽  
Ataxia Telangiectasia ◽  
Hair Follicles ◽  
Ataxia Telangiectasia Mutated ◽  
Independent Manner ◽  
Li Fraumeni Syndrome ◽  
Cycle Arrest ◽  
Induced Apoptosis

ABSTRACT In response to ionizing radiation (IR), the tumor suppressor p53 is stabilized and promotes either cell cycle arrest or apoptosis. Chk2 activated by IR contributes to this stabilization, possibly by direct phosphorylation. Like p53, Chk2 is mutated in patients with Li-Fraumeni syndrome. Since the ataxia telangiectasia mutated (ATM) gene is required for IR-induced activation of Chk2, it has been assumed that ATM and Chk2 act in a linear pathway leading to p53 activation. To clarify the role of Chk2 in tumorigenesis, we generated gene-targeted Chk2-deficient mice. Unlike ATM−/− and p53−/− mice, Chk2−/− mice do not spontaneously develop tumors, although Chk2 does suppress 7,12-dimethylbenzanthracene-induced skin tumors. Tissues from Chk2−/− mice, including those from the thymus, central nervous system, fibroblasts, epidermis, and hair follicles, show significant defects in IR-induced apoptosis or impaired G1/S arrest. Quantitative comparison of the G1/S checkpoint, apoptosis, and expression of p53 proteins in Chk2−/− versus ATM−/− thymocytes suggested that Chk2 can regulate p53-dependent apoptosis in an ATM-independent manner. IR-induced apoptosis was restored in Chk2−/− thymocytes by reintroduction of the wild-type Chk2 gene but not by a Chk2 gene in which the sites phosphorylated by ATM and ataxia telangiectasia and rad3 + related (ATR) were mutated to alanine. ATR may thus selectively contribute to p53-mediated apoptosis. These data indicate that distinct pathways regulate the activation of p53 leading to cell cycle arrest or apoptosis.

scholarly journals Defect in Multiple Cell Cycle Checkpoints in Ataxia-Telangiectasia Postirradiation

1996 ◽  
Vol 271 (34) ◽  
pp. 20486-20493 ◽  
Author(s):  
Heather Beamish ◽  
Richard Williams ◽  
Philip Chen ◽  
Martin F. Lavin
Keyword(s):  
Cell Cycle ◽  
Ataxia Telangiectasia ◽  
Cell Cycle Checkpoints ◽  
Multiple Cell

scholarly journals Targeting EZH2 in Multiple Myeloma—Multifaceted Anti-Tumor Activity

Epigenomes ◽  
2018 ◽  
Vol 2 (3) ◽  
pp. 16 ◽  
Author(s):  
Mohammad Alzrigat ◽  
Helena Jernberg-Wiklund ◽  
Jonathan Licht
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Tumor Suppressor ◽  
Current Knowledge ◽  
Cell Cycle Control ◽  
Cellular Transformation ◽  
Therapeutic Modality ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Adhesion Properties

The enhancer of zeste homolog 2 (EZH2) is the enzymatic subunit of the polycomb repressive complex 2 (PRC2) that exerts important functions during normal development as well as disease. PRC2 through EZH2 tri-methylates histone H3 lysine tail residue 27 (H3K27me3), a modification associated with repression of gene expression programs related to stem cell self-renewal, cell cycle, cell differentiation, and cellular transformation. EZH2 is deregulated and subjected to gain of function or loss of function mutations, and hence functions as an oncogene or tumor suppressor gene in a context-dependent manner. The development of highly selective inhibitors against the histone methyltransferase activity of EZH2 has also contributed to insight into the role of EZH2 and PRC2 in tumorigenesis, and their potential as therapeutic targets in cancer. EZH2 can function as an oncogene in multiple myeloma (MM) by repressing tumor suppressor genes that control apoptosis, cell cycle control and adhesion properties. Taken together these findings have raised the possibility that EZH2 inhibitors could be a useful therapeutic modality in MM alone or in combination with other targeted agents in MM. Therefore, we review the current knowledge on the regulation of EZH2 and its biological impact in MM, the anti-myeloma activity of EZH2 inhibitors and their potential as a targeted therapy in MM.

scholarly journals Human Cytomegalovirus IE1-72 Activates Ataxia Telangiectasia Mutated Kinase and a p53/p21-Mediated Growth Arrest Response

2005 ◽  
Vol 79 (17) ◽  
pp. 11467-11475 ◽  
Author(s):  
Jonathan P. Castillo ◽  
Fiona M. Frame ◽  
Harry A. Rogoff ◽  
Mary T. Pickering ◽  
Andrew D. Yurochko ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Human Cytomegalovirus ◽  
Ataxia Telangiectasia ◽  
Cell Cycle Progression ◽  
Hcmv Infection ◽  
S Phase ◽  
Nuclear Accumulation ◽  
Ataxia Telangiectasia Mutated ◽  
P53 Response ◽  
Nuclear Shuttling

ABSTRACT Human cytomegalovirus (HCMV) encodes several proteins that can modulate components of the cell cycle machinery. The UL123 gene product, IE1-72, binds the Rb-related, p107 protein and relieves its repression of E2F-responsive promoters; however, it is unable to induce quiescent cells to enter S phase in wild-type (p53 +/+ ) cells. IE1-72 also induces p53 accumulation through an unknown mechanism. We present here evidence suggesting that IE1-72 may activate the p53 pathway by increasing the levels of p19Arf and by inducing the phosphorylation of p53 at Ser15. Phosphorylation of this residue by IE1-72 expression alone or HCMV infection is found to be dependent on the ataxia-telangiectasia mutated kinase. IE2-86 expression leads to p53 phosphorylation and may contribute to this phenotype in HCMV-infected cells. We also found that IE1-72 promotes p53 nuclear accumulation by abrogating p53 nuclear shuttling. These events result in the stimulation of p53 activity, leading to a p53- and p21-dependent inhibition of cell cycle progression from G1 to S phase in cells transiently expressing IE1-72. Thus, like many of the small DNA tumor viruses, the first protein expressed upon HCMV infection activates a p53 response by the host cell.

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