Multiple roles of ATM in monitoring and maintaining DNA integrity

Derheimer, Frederick A.; Kastan, Michael B.

doi:10.1016/j.febslet.2010.05.031

Cited by 212 publications

(173 citation statements)

References 71 publications

(86 reference statements)

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“…Coupled with the observation that p30 enhanced cell survival following genotoxic stress (Fig. 1), we hypothesized that p30 expression may modulate levels of pATM to prevent triggering apoptosis, promoting cell survival of viral infected cells (34,35). Our data suggest a role for p30 in modifying cellular response to DNA damage, influencing the amount of ATM available to induce apoptosis.…”

Section: Htlv-1 P30 Promotes Cell Survival In the Presence Of Genotoxmentioning

confidence: 87%

Human T-lymphotropic Virus Type 1 p30 Interacts with REGγ and Modulates ATM (Ataxia Telangiectasia Mutated) to Promote Cell Survival

Anupam¹,

Datta²,

Kesic³

et al. 2011

Journal of Biological Chemistry

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Human T-lymphotropic virus type 1 (HTLV-1) is a causative agent of adult T cell leukemia/lymphoma and a variety of inflammatory disorders. HTLV-1 encodes a nuclear localizing protein, p30, that selectively alters viral and cellular gene expression, activates G 2 -M cell cycle checkpoints, and is essential for viral spread. Here, we used immunoprecipitation and affinity pulldown of ectopically expressed p30 coupled with mass spectrometry to identify cellular binding partners of p30. Our data indicate that p30 specifically binds to cellular ATM (ataxia telangiectasia mutated) and REG␥ (a nuclear 20 S proteasome activator). Under conditions of genotoxic stress, p30 expression was associated with reduced levels of ATM and increased cell survival. Knockdown or overexpression of REG␥ paralleled p30 expression, suggesting an unexpected enhancement of p30 expression in the presence of REG␥. Finally, size exclusion chromatography revealed the presence of p30 in a high molecular mass complex along with ATM and REG␥. On the basis of our findings, we propose that HTLV-1 p30 interacts with ATM and REG␥ to increase viral spread by facilitating cell survival. Human T-lymphotropic virus type 1 (HTLV-1)2 is a complex deltaretrovirus and the first reported human retrovirus linked to malignancy (1, 2). It is estimated that ϳ20 million people worldwide are infected with HTLV-1 (3). Approximately five percent of these infected individuals will develop one of a variety of immunopathologic or neoplastic conditions (reviewed in Ref. 4). Two well characterized pathological conditions associated with HTLV-1 infection are adult T cell leukemia/lymphoma, a highly aggressive T cell malignancy, and HTLV-1-associated myelopathy/tropical spastic paraparesis, an immune-mediated neurodegenerative condition (5, 6). The prolonged latency between acquisition of infection and disease expression indicates a highly regulated host-virus relationship that promotes survival of HTLV-1-infected cell reservoirs.HTLV-1 contains genes that encode typical retroviral structural and enzymatic proteins such as Gag, Pol, and Env, as well as regulatory proteins Tax and Rex (reviewed in Ref. 4). The pX region of HTLV-1 contains open reading frames that also encode for various nonstructural proteins (p12, p13, HBZ, and p30) that are essential to viral transmission and spread (7-12).HTLV-1 p30 is a nuclear and nucleolar localizing protein encoded by a doubly spliced mRNA from ORF II of the pX region of the viral genome (13, 14) that modulates viral and cellular gene expression by transcriptional and post-translational mechanisms (14, 15). HTLV-1-infected individuals produce cytotoxic T cells and antibodies to p30 peptides (16,17). We reported that p30 differentially modulates the activity of HTLV-1 promoter-driven reporter genes (18) through its interaction with the transcriptional coactivator p300 (19). In Jurkat T cells, p30 alters the expression of a variety of cellular genes and also enhances signal pathways important for T cell growth and survival (20). Ectopical...

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Section: Htlv-1 P30 Promotes Cell Survival In the Presence Of Genotoxmentioning

confidence: 87%

Human T-lymphotropic Virus Type 1 p30 Interacts with REGγ and Modulates ATM (Ataxia Telangiectasia Mutated) to Promote Cell Survival

Anupam¹,

Datta²,

Kesic³

et al. 2011

Journal of Biological Chemistry

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“…ATM is a serine/threonine kinase which belongs to phosphoinositide 3-kinase (PI3K)-related protein kinase (PIKK) family [6]. ATM plays a pivotal role in cellular and molecular response to DSBs, such as cell cycle checkpoint and DSB repair [6,7]. In G1 checkpoint, ATM transduces DSB signals to Chk2 and p53 by phosphorylation, and induces transient delay of S phase entry at earlier times and more sustained blockage of S phase entry at later times, respectively [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Mode of ATM-dependent suppression of chromosome translocation

Yamauchi

Suzuki

Oka

et al. 2011

Biochemical and Biophysical Research Communications

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It is well documented that deficiency in ataxia telangiectasia mutated (ATM) protein leads to elevated frequency of chromosome translocation, however, it remains poorly understood how ATM suppresses translocation frequency. In the present study, we addressed the mechanism of ATM-dependent suppression of translocation frequency. To know frequency of translocation events in a whole genome at once, we performed centromere/telomere FISH and scored dicentric chromosomes, because dicentric and translocation occur with equal frequency and by identical mechanism. By centromere/telomere FISH analysis, we confirmed that chemical inhibition orRNAi-mediated knockdown of ATM causes 2~2.5-fold increase in dicentric frequency at first mitosis after 2 Gy of gamma-irradiation in G0/G1. The FISH analysis revealed that ATM/p53-dependent G1 checkpoint suppresses dicentric frequency, since RNAi-mediated knockdown of p53 elevated dicentric frequency by 1.5-fold. We found ATM also suppresses dicentric occurrence independently of its checkpoint role, as ATM inhibitor showed additional effect on dicentric frequency in the context of p53 depletion and Chk1/2 inactivation. Epistasis analysis using chemical inhibitors revealed that ATM kinase functions in the same pathway that requires kinase activity of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to suppress dicentric frequency. From the results in the present study, we conclude that ATM minimizes translocation frequency through its commitment to G1 checkpoint and DNA double-strand break repair pathway that requires kinase activity of DNA-PKcs.

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“…ATM belongs to the class of caretaker tumour suppressor genes that defend genome integrity (Levitt & Hickson 2002). It is involved in multiple cellular processes that occur in response to DNA damage, including cell cycle check point control, DNA repair and apoptosis (Derheimer & Kastan 2010, Shiloh & Ziv 2013.…”

Section: :9mentioning

confidence: 99%

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Domenico

Wiedmer

Perren

2017

Endocrine-Related Cancer

106

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Neuroendocrine tumours (NET) of the gastrointestinal tract and the lung are a rare and heterogeneous group of tumours. The molecular characterization and the clinical classification of these tumours have been evolving slowly and show differences according to organs of origin. Novel technologies such as next-generation sequencing revealed new molecular aspects of NET over the last years. Notably, whole-exome/genome sequencing (WES/WGS) approaches underlined the very low mutation rate of well-differentiated NET of all organs compared to other malignancies, while the engagement of epigenetic changes in driving NET evolution is emerging. Indeed, mutations in genes encoding for proteins directly involved in chromatin remodelling, such as DAXX and ATRX are a frequent event in NET. Epigenetic changes are reversible and targetable; therefore, an attractive target for treatment. The discovery of the mechanisms underlying the epigenetic changes and the implication on gene and miRNA expression in the different subgroups of NET may represent a crucial change in the diagnosis of this disease, reveal new therapy targets and identify predictive markers. Molecular profiles derived from omics data including DNA mutation, methylation, gene and miRNA expression have already shown promising results in distinguishing clinically and molecularly different subtypes of NET. In this review, we recapitulate the major genetic and epigenetic characteristics of pancreatic, lung and small intestinal NET and the affected pathways. We also discuss potential epigenetic mechanisms leading to NET development.

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Multiple roles of ATM in monitoring and maintaining DNA integrity

Cited by 212 publications

References 71 publications

Human T-lymphotropic Virus Type 1 p30 Interacts with REGγ and Modulates ATM (Ataxia Telangiectasia Mutated) to Promote Cell Survival

Human T-lymphotropic Virus Type 1 p30 Interacts with REGγ and Modulates ATM (Ataxia Telangiectasia Mutated) to Promote Cell Survival

Mode of ATM-dependent suppression of chromosome translocation

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

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