ATM: Functions of ATM Kinase and Its Relevance to Hereditary Tumors

Ataxia–telangiectasia mutated (ATM) functions as a key initiator and coordinator of DNA damage and cellular stress responses. ATM signaling pathways contain many downstream targets that regulate multiple important cellular processes, including DNA damage repair, apoptosis, cell cycle arrest, oxidative sensing, and proliferation. Over the past few decades, associations between germline ATM pathogenic variants and cancer risk have been reported, particularly for breast and pancreatic cancers. In addition, given that ATM plays a critical role in repairing double-strand breaks, inhibiting other DNA repair pathways could be a synthetic lethal approach. Based on this rationale, several DNA damage response inhibitors are currently being tested in ATM-deficient cancers. In this review, we discuss the current knowledge related to the structure of the ATM gene, function of ATM kinase, clinical significance of ATM germline pathogenic variants in patients with hereditary cancers, and ongoing efforts to target ATM for the benefit of cancer patients.

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PARP inhibitors in gastric cancer: beacon of hope

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-02005-6 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Yali Wang ◽

Kun Zheng ◽

Yongbiao Huang ◽

Hua Xiong ◽

Jinfang Su ◽

...

Keyword(s):

Gastric Cancer ◽

Dna Damage ◽

Dna Repair ◽

Genome Instability ◽

Parp Inhibitors ◽

Synthetic Lethal ◽

Strand Breaks ◽

Cellular Processes ◽

Single Strand Breaks ◽

Damage Repair

AbstractDefects in the DNA damage response (DDR) can lead to genome instability, producing mutations or aberrations that promote the development and progression of cancer. But it also confers such cells vulnerable to cell death when they inhibit DNA damage repair. Poly (ADP-ribose) polymerase (PARP) plays a central role in many cellular processes, including DNA repair, replication, and transcription. PARP induces the occurrence of poly (ADP-ribosylation) (PARylation) when DNA single strand breaks (SSB) occur. PARP and various proteins can interact directly or indirectly through PARylation to regulate DNA repair. Inhibitors that directly target PARP have been found to block the SSB repair pathway, triggering homologous recombination deficiency (HRD) cancers to form synthetic lethal concepts that represent an anticancer strategy. It has therefore been investigated in many cancer types for more effective anti-cancer strategies, including gastric cancer (GC). This review describes the antitumor mechanisms of PARP inhibitors (PARPis), and the preclinical and clinical progress of PARPis as monotherapy and combination therapy in GC.

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Arginine Decarboxylase Is Essential for Pneumococcal Stress Responses

Pathogens ◽

10.3390/pathogens10030286 ◽

2021 ◽

Vol 10 (3) ◽

pp. 286

Author(s):

Mary Frances Nakamya ◽

Moses B. Ayoola ◽

Leslie A. Shack ◽

Mirghani Mohamed ◽

Edwin Swiatlo ◽

...

Keyword(s):

Stress Responses ◽

Critical Role ◽

Acid Stress ◽

Arginine Decarboxylase ◽

Arginine Deiminase ◽

Dependent Manner ◽

Cellular Processes ◽

Opportunistic Human Pathogen ◽

Thiol Peroxidase ◽

The Impact

Polyamines such as putrescine, cadaverine, and spermidine are small cationic molecules that play significant roles in cellular processes, including bacterial stress responses and host–pathogen interactions. Streptococcus pneumoniae is an opportunistic human pathogen, which causes several diseases that account for significant morbidity and mortality worldwide. As it transits through different host niches, S. pneumoniae is exposed to and must adapt to different types of stress in the host microenvironment. We earlier reported that S. pneumoniae TIGR4, which harbors an isogenic deletion of an arginine decarboxylase (ΔspeA), an enzyme that catalyzes the synthesis of agmatine in the polyamine synthesis pathway, has a reduced capsule. Here, we report the impact of arginine decarboxylase deletion on pneumococcal stress responses. Our results show that ΔspeA is more susceptible to oxidative, nitrosative, and acid stress compared to the wild-type strain. Gene expression analysis by qRT-PCR indicates that thiol peroxidase, a scavenger of reactive oxygen species and aguA from the arginine deiminase system, could be important for peroxide stress responses in a polyamine-dependent manner. Our results also show that speA is essential for endogenous hydrogen peroxide and glutathione production in S. pneumoniae. Taken together, our findings demonstrate the critical role of arginine decarboxylase in pneumococcal stress responses that could impact adaptation and survival in the host.

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The emerging role of RNAs in DNA damage repair

Cell Death and Differentiation ◽

10.1038/cdd.2017.16 ◽

2017 ◽

Vol 24 (4) ◽

pp. 580-587 ◽

Cited By ~ 18

Author(s):

Ben R Hawley ◽

Wei-Ting Lu ◽

Ania Wilczynska ◽

Martin Bushell

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Critical Role ◽

Repair Process ◽

Rna Molecules ◽

Processing Enzymes ◽

Damage Repair ◽

New Findings ◽

Integral Role ◽

Repair Mechanisms

Abstract Many surveillance and repair mechanisms exist to maintain the integrity of our genome. All of the pathways described to date are controlled exclusively by proteins, which through their enzymatic activities identify breaks, propagate the damage signal, recruit further protein factors and ultimately resolve the break with little to no loss of genetic information. RNA is known to have an integral role in many cellular pathways, but, until very recently, was not considered to take part in the DNA repair process. Several reports demonstrated a conserved critical role for RNA-processing enzymes and RNA molecules in DNA repair, but the biogenesis of these damage-related RNAs and their mechanisms of action remain unknown. We will explore how these new findings challenge the idea of proteins being the sole participants in the response to DNA damage and reveal a new and exciting aspect of both DNA repair and RNA biology.

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Assessing BRCA1 activity in DNA damage repair using human induced pluripotent stem cells as an approach to assist classification of BRCA1 variants of uncertain significance

PLoS ONE ◽

10.1371/journal.pone.0260852 ◽

2021 ◽

Vol 16 (12) ◽

pp. e0260852

Author(s):

Meryem Ozgencil ◽

Julian Barwell ◽

Marc Tischkowitz ◽

Louise Izatt ◽

Ian Kesterton ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Repair ◽

Ips Cells ◽

Variants Of Uncertain Significance ◽

Cellular Models ◽

Pathogenic Variants ◽

Damage Repair ◽

Uncertain Significance ◽

Induced Pluripotent ◽

The Impact

Establishing a universally applicable protocol to assess the impact of BRCA1 variants of uncertain significance (VUS) expression is a problem which has yet to be resolved despite major progresses have been made. The numerous difficulties which must be overcome include the choices of cellular models and functional assays. We hypothesised that the use of induced pluripotent stem (iPS) cells might facilitate the standardisation of protocols for classification, and could better model the disease process. We generated eight iPS cell lines from patient samples expressing either BRCA1 pathogenic variants, non-pathogenic variants, or BRCA1 VUSs. The impact of these variants on DNA damage repair was examined using a ɣH2AX foci formation assay, a Homologous Repair (HR) reporter assay, and a chromosome abnormality assay. Finally, all lines were tested for their ability to differentiate into mammary lineages in vitro. While the results obtained from the two BRCA1 pathogenic variants were consistent with published data, some other variants exhibited differences. The most striking of these was the BRCA1 variant Y856H (classified as benign), which was unexpectedly found to present a faulty HR repair pathway, a finding linked to the presence of an additional variant in the ATM gene. Finally, all lines were able to differentiate first into mammospheres, and then into more advanced mammary lineages expressing luminal- or basal-specific markers. This study stresses that BRCA1 genetic analysis alone is insufficient to establish a reliable and functional classification for assessment of clinical risk, and that it cannot be performed without considering the other genetic aberrations which may be present in patients. The study also provides promising opportunities for elucidating the physiopathology and clinical evolution of breast cancer, by using iPS cells.

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S-Nitrosoglutathione Reductase—The Master Regulator of Protein S-Nitrosation in Plant NO Signaling

Plants ◽

10.3390/plants8020048 ◽

2019 ◽

Vol 8 (2) ◽

pp. 48 ◽

Cited By ~ 25

Author(s):

Jana Jahnová ◽

Lenka Luhová ◽

Marek Petřivalský

Keyword(s):

Stress Responses ◽

Current Knowledge ◽

Protein S ◽

Defense Responses ◽

Reactive Nitrogen ◽

Cellular Processes ◽

Protein Thiols ◽

Key Enzyme ◽

No Signaling ◽

Cysteine Thiols

S-nitrosation has been recognized as an important mechanism of protein posttranslational regulations, based on the attachment of a nitroso group to cysteine thiols. Reversible S-nitrosation, similarly to other redox-base modifications of protein thiols, has a profound effect on protein structure and activity and is considered as a convergence of signaling pathways of reactive nitrogen and oxygen species. In plant, S-nitrosation is involved in a wide array of cellular processes during normal development and stress responses. This review summarizes current knowledge on S-nitrosoglutathione reductase (GSNOR), a key enzyme which regulates intracellular levels of S-nitrosoglutathione (GSNO) and indirectly also of protein S-nitrosothiols. GSNOR functions are mediated by its enzymatic activity, which catalyzes irreversible GSNO conversion to oxidized glutathione within the cellular catabolism of nitric oxide. GSNOR is involved in the maintenance of balanced levels of reactive nitrogen species and in the control of cellular redox state. Multiple functions of GSNOR in plant development via NO-dependent and -independent signaling mechanisms and in plant defense responses to abiotic and biotic stress conditions have been uncovered. Extensive studies of plants with down- and upregulated GSNOR, together with application of transcriptomics and proteomics approaches, seem promising for new insights into plant S-nitrosothiol metabolism and its regulation.

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Fungal Production and Manipulation of Plant Hormones

Current Medicinal Chemistry ◽

10.2174/0929867324666170314150827 ◽

2018 ◽

Vol 25 (2) ◽

pp. 253-267 ◽

Cited By ~ 8

Author(s):

Sandra Fonseca ◽

Dhanya Radhakrishnan ◽

Kalika Prasad ◽

Andrea Chini

Keyword(s):

Stress Responses ◽

Current Knowledge ◽

Critical Role ◽

Plant Defence ◽

Pathogenic Fungi ◽

Plant Responses ◽

Defensive Strategies ◽

Hormone Balance ◽

Living Organisms

Living organisms are part of a highly interconnected web of interactions, characterised by species nurturing, competing, parasitizing and preying on one another. Plants have evolved cooperative as well as defensive strategies to interact with neighbour organisms. Among these, the plant-fungus associations are very diverse, ranging from pathogenic to mutualistic. Our current knowledge of plant-fungus interactions suggests a sophisticated coevolution to ensure dynamic plant responses to evolving fungal mutualistic/pathogenic strategies. The plant-fungus communication relies on a rich chemical language. To manipulate the plant defence mechanisms, fungi produce and secrete several classes of biomolecules, whose modeof- action is largely unknown. Upon perception of the fungi, plants produce phytohormones and a battery of secondary metabolites that serve as defence mechanism against invaders or to promote mutualistic associations. These mutualistic chemical signals can be co-opted by pathogenic fungi for their own benefit. Among the plant molecules regulating plant-fungus interaction, phytohormones play a critical role since they modulate various aspects of plant development, defences and stress responses. Intriguingly, fungi can also produce phytohormones, although the actual role of fungalproduced phytohormones in plant-fungus interactions is poorly understood. Here, we discuss the recent advances in fungal production of phytohormone, their putative role as endogenous fungal signals and how fungi manipulate plant hormone balance to their benefits.

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Correction of ATM mutations in iPS cells from two ataxia-telangiectasia patients restores DNA damage and oxidative stress responses

Human Molecular Genetics ◽

10.1093/hmg/ddaa023 ◽

2020 ◽

Vol 29 (6) ◽

pp. 990-1001 ◽

Cited By ~ 5

Author(s):

Dmitry A Ovchinnikov ◽

Sarah L Withey ◽

Hannah C Leeson ◽

U Wang Lei ◽

Ashmitha Sundarrajan ◽

...

Keyword(s):

Oxidative Stress ◽

Dna Damage ◽

Stress Responses ◽

Ataxia Telangiectasia ◽

Compound Heterozygous ◽

Gene Correction ◽

Atm Kinase ◽

Atm Protein ◽

Induced Apoptosis ◽

And Oxidative Stress

Abstract Patients with ataxia-telangiectasia (A-T) lack a functional ATM kinase protein and exhibit defective repair of DNA double-stranded breaks and response to oxidative stress. We show that CRISPR/Cas9-assisted gene correction combined with piggyBac (PB) transposon-mediated excision of the selection cassette enables seamless restoration of functional ATM alleles in induced pluripotent stem cells from an A-T patient carrying compound heterozygous exonic missense/frameshift mutations, and from a patient with a homozygous splicing acceptor mutation of an internal coding exon. We show that the correction of one allele restores expression of ~ 50% of full-length ATM protein and ameliorates DNA damage-induced activation (auto-phosphorylation) of ATM and phosphorylation of its downstream targets, KAP-1 and H2AX. Restoration of ATM function also normalizes radiosensitivity, mitochondrial ROS production and oxidative-stress-induced apoptosis levels in A-T iPSC lines, demonstrating that restoration of a single ATM allele is sufficient to rescue key ATM functions. Our data further show that despite the absence of a functional ATM kinase, homology-directed repair and seamless correction of a pathogenic ATM mutation is possible. The isogenic pairs of A-T and gene-corrected iPSCs described here constitute valuable tools for elucidating the role of ATM in ageing and A-T pathogenesis.

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Suppression of MicroRNA 424 Levels by Human Papillomaviruses Is Necessary for Differentiation-Dependent Genome Amplification

Journal of Virology ◽

10.1128/jvi.01712-17 ◽

2017 ◽

Vol 91 (24) ◽

Cited By ~ 10

Author(s):

Shiyuan Hong ◽

Shouqiang Cheng ◽

William Songock ◽

Jason Bodily ◽

Laimonis A. Laimins

Keyword(s):

Dna Damage ◽

Critical Role ◽

Human Papillomaviruses ◽

Expression Vectors ◽

Hpv E6 ◽

Damage Repair ◽

Undifferentiated Cells ◽

Efficient Replication ◽

E6 And E7 ◽

E7 Proteins

ABSTRACT High-risk human papillomaviruses (HPVs) link their life cycle to epithelial differentiation and require activation of DNA damage pathways for efficient replication. HPVs modulate the expression of cellular transcription factors, as well as cellular microRNAs (miRNAs) to control these activities. One miRNA that has been reported to be repressed in HPV-positive cancers of the cervix and oropharynx is miR-424. Our studies show that miR-424 levels are suppressed in cell lines that stably maintain HPV 31 or 16 episomes, as well as cervical cancer lines that contain integrated genomes such as SiHa. Introduction of expression vectors for miR-424 reduced both the levels of HPV genomes in undifferentiated cells and amplification upon differentiation. Our studies show that the levels of two putative targets of miR-424 that function in DNA damage repair, CHK1 and Wee1, are suppressed in HPV-positive cells, providing an explanation for why this microRNA is targeted in HPV-positive cells. IMPORTANCE We describe here for the first time a critical role for miR-424 in the regulation of HPV replication. HPV E6 and E7 proteins suppress the levels of miR-424, and this is important for controlling the levels of CHK1, which plays a central role in viral replication.

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A Role for Bradyrhizobium japonicum ECF16 Sigma Factor EcfS in the Formation of a Functional Symbiosis with Soybean

Molecular Plant-Microbe Interactions ◽

10.1094/mpmi-07-11-0188 ◽

2012 ◽

Vol 25 (1) ◽

pp. 119-128 ◽

Cited By ~ 7

Author(s):

S. B. Stockwell ◽

L. Reutimann ◽

M. L. Guerinot

Keyword(s):

Stress Responses ◽

Sigma Factor ◽

Bradyrhizobium Japonicum ◽

Critical Role ◽

Negative Regulator ◽

In Planta ◽

Cellular Processes ◽

Core Enzyme ◽

Σ Factor ◽

Target Promoters

Alternative sigma (σ) factors, proteins that recruit RNA polymerase core enzyme to target promoters, are one mechanism by which bacteria transcriptionally regulate groups of genes in response to environmental stimuli. A class of σ70 proteins, termed extracytoplasmic function (ECF) σ factors, are involved in cellular processes such as bacterial stress responses and virulence. Here, we describe an ECF16 σ factor, EcfS (Blr4928) from the gram-negative soil bacterium Bradyrhizobium japonicum USDA110, that plays a critical role in the establishment of a functional symbiosis with soybean. Nonpolar insertional mutants of ecfS form immature nodules that do not fix nitrogen, a defect that can be successfully complemented by expression of ecfS. Overexpression of the cocistronic gene, tmrS (blr4929), phenocopies the ecfS mutant in planta and, therefore, we propose that TmrS is a negative regulator of EcfS, a determination consistent with the prediction that it encodes an anti-σ factor. Microarray analysis of the ecfS mutant and tmrS overexpressor was used to identify 40 transcripts misregulated in both strains. These transcripts primarily encode proteins of unknown and transport-related functions and may provide insights into the symbiotic defect in these strains.

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DNA damage-specific effects of Tel1/ATM and γH2A/γH2AX on checkpoint signaling inSaccharomyces cerevisiae

10.1101/572271 ◽

2019 ◽

Author(s):

Jasmine Siler ◽

Na Guo ◽

Zhengfeng Liu ◽

Yuhua Qin ◽

Xin Bi

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Topoisomerase I ◽

Cell Cycle Progression ◽

Dynamic Balance ◽

Dna Lesions ◽

Atm Kinase ◽

Checkpoint Signaling ◽

Specific Effects ◽

Damage Repair

AbstractDNA lesions trigger the activation of DNA damage checkpoints (DDCs) that stop cell cycle progression and promote DNA damage repair.Saccharomyces cerevisiaeTel1 is a homolog of mammalian ATM kinase that plays an auxiliary role in DDC signaling. γH2A, equivalent to γH2AX in mammals, is an early chromatin mark induced by DNA damage that is recognized by a group of DDC and DNA repair factors. We find that both Tel1 and γH2A negatively impact G2/M checkpoint in response to DNA topoisomerase I poison camptothecin independently of each other. γH2A also negatively regulates DDC induced by DNA alkylating agent methyl methanesulfonate. These results, together with prior findings demonstrating positive or no roles of Tel1 and γH2A in DDC in response to other DNA damaging agents such as phleomycin and ionizing radiation, suggest that Tel1 and γH2A have DNA damage-specific effects on DDC. We present data indicating that Tel1 acts in the same pathway as Mre11-Rad50-Xrs2 complex to suppress CPT induced DDC possibly by repairing topoisomerase I-DNA crosslink. On the other hand, we find evidence consistent with the notion that γH2A regulates DDC by mediating the competitive recruitment of DDC mediator Rad9 and DNA repair factor Rtt107 to sites of DNA damage. We propose that γH2A serves to create a dynamic balance between DDC and DNA repair that is influenced by the nature of DNA damage.

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