RTT109 AND Fun30 proteins mediate epigenetic regulation of the DNA damage response pathway in C. albicans

Fun30, an ATP-dependent chromatin remodeller, from S. cerevisiae mediates both regulation of gene expression as well as DNA damage response/repair. In this paper, we have characterized the biochemical and physiological function of Fun30 from the opportunistic fungi, C. albicans. Biochemically, the protein shows DNA-stimulated ATPase activity. Physiologically, the protein co-regulates transcription of RTT109, TEL1, MEC1, and SNF2-genes that encode for proteins involved in DNA damage response and repair pathway. The expression of FUN30, in turn, is regulated by histone H3 acetylation catalysed by Rtt109 encoded by RTT109. The RTT109Hz/FUN30Hz mutant strain shows sensitivity to oxidative stress and resistance to MMS as compared to the wild type strain. Quantitative PCR showed that the sensitivity to oxidative stress results from downregulation of MEC1, RAD9, MRC1 and RAD5 expression; ChIP experiments showed Fun30 but not H3ac regulates the expression of these genes in response to oxidative stress. In contrast, on treatment with MMS, the expression of RAD9 is upregulated and this upregulation is co-regulated by both Fun30 and H3 acetylation catalysed by Rtt109. Thus, Fun30 and H3 acetylation mediate the response of the fungal cell to genotoxic agents in C. albicans by regulating the expression of DNA damage response and repair pathway genes.

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Characterization of the role of the DNA damage response pathway in parvoviral replication

10.32469/10355/15925 ◽

2012 ◽

Author(s):

Richard Adeyemi

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Damage Response ◽

Dna Damage Response Pathway

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DNA Damage Response Pathway and Replication Fork Stress During Oligonucleotide Directed Gene Editing

Molecular Therapy — Nucleic Acids ◽

10.1038/mtna.2012.9 ◽

2012 ◽

Vol 1 ◽

pp. e18 ◽

Cited By ~ 5

Author(s):

Melissa Bonner ◽

Bryan Strouse ◽

Mindy Applegate ◽

Paula Livingston ◽

Eric B Kmiec

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Replication Fork ◽

Gene Editing ◽

Damage Response ◽

Dna Damage Response Pathway

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Structural basis of γH2AX recognition by human PTIP BRCT5-BRCT6 domains in the DNA damage response pathway

FEBS Letters ◽

10.1016/j.febslet.2011.10.045 ◽

2011 ◽

Vol 585 (24) ◽

pp. 3874-3879 ◽

Cited By ~ 20

Author(s):

Wei Yan ◽

Zhenhua Shao ◽

Fudong Li ◽

Liwen Niu ◽

Yunyu Shi ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Structural Basis ◽

Damage Response ◽

Dna Damage Response Pathway

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DNA Damage Response and Oxidative Stress in Systemic Autoimmunity

International Journal of Molecular Sciences ◽

10.3390/ijms21010055 ◽

2019 ◽

Vol 21 (1) ◽

pp. 55 ◽

Cited By ~ 8

Author(s):

Vassilis L. Souliotis ◽

Nikolaos I. Vlachogiannis ◽

Maria Pappa ◽

Alexandra Argyriou ◽

Panagiotis A. Ntouros ◽

...

Keyword(s):

Oxidative Stress ◽

Immune Response ◽

Dna Damage ◽

Autoimmune Diseases ◽

Dna Damage Response ◽

Lupus Erythematosus ◽

Mononuclear Cells ◽

Tissue Injury ◽

Systemic Autoimmune Diseases ◽

Damage Response

The DNA damage response and repair (DDR/R) network, a sum of hierarchically structured signaling pathways that recognize and repair DNA damage, and the immune response to endogenous and/or exogenous threats, act synergistically to enhance cellular defense. On the other hand, a deregulated interplay between these systems underlines inflammatory diseases including malignancies and chronic systemic autoimmune diseases, such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Patients with these diseases are characterized by aberrant immune response to self-antigens with widespread production of autoantibodies and multiple-tissue injury, as well as by the presence of increased oxidative stress. Recent data demonstrate accumulation of endogenous DNA damage in peripheral blood mononuclear cells from these patients, which is related to (a) augmented DNA damage formation, at least partly due to the induction of oxidative stress, and (b) epigenetically regulated functional abnormalities of fundamental DNA repair mechanisms. Because endogenous DNA damage accumulation has serious consequences for cellular health, including genomic instability and enhancement of an aberrant immune response, these results can be exploited for understanding pathogenesis and progression of systemic autoimmune diseases, as well as for the development of new treatments.

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580. Insight into the Mechanism of Increased Transduction of AAV Vectors with Ad Proteins E1B55k/E4orf6 and Generalization to Other Substrates of the Cellular DNA Damage Response Pathway

Molecular Therapy ◽

10.1016/s1525-0016(16)36384-5 ◽

2012 ◽

Vol 20 ◽

pp. S225

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Damage Response ◽

Cellular Dna ◽

Dna Damage Response Pathway ◽

Insight Into

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APE2 Is a General Regulator of the ATR-Chk1 DNA Damage Response Pathway to Maintain Genome Integrity in Pancreatic Cancer Cells

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.738502 ◽

2021 ◽

Vol 9 ◽

Author(s):

Md Akram Hossain ◽

Yunfeng Lin ◽

Garrett Driscoll ◽

Jia Li ◽

Anne McMahon ◽

...

Keyword(s):

Oxidative Stress ◽

Pancreatic Cancer ◽

Dna Damage ◽

Cancer Cells ◽

Dna Damage Response ◽

Human Pancreatic Cancer ◽

Genome Integrity ◽

Pancreatic Cancer Cells ◽

Damage Response ◽

Egg Extracts

The maintenance of genome integrity and fidelity is vital for the proper function and survival of all organisms. Recent studies have revealed that APE2 is required to activate an ATR-Chk1 DNA damage response (DDR) pathway in response to oxidative stress and a defined DNA single-strand break (SSB) in Xenopus laevis egg extracts. However, it remains unclear whether APE2 is a general regulator of the DDR pathway in mammalian cells. Here, we provide evidence using human pancreatic cancer cells that APE2 is essential for ATR DDR pathway activation in response to different stressful conditions including oxidative stress, DNA replication stress, and DNA double-strand breaks. Fluorescence microscopy analysis shows that APE2-knockdown (KD) leads to enhanced γH2AX foci and increased micronuclei formation. In addition, we identified a small molecule compound Celastrol as an APE2 inhibitor that specifically compromises the binding of APE2 but not RPA to ssDNA and 3′-5′ exonuclease activity of APE2 but not APE1. The impairment of ATR-Chk1 DDR pathway by Celastrol in Xenopus egg extracts and human pancreatic cancer cells highlights the physiological significance of Celastrol in the regulation of APE2 functionalities in genome integrity. Notably, cell viability assays demonstrate that APE2-KD or Celastrol sensitizes pancreatic cancer cells to chemotherapy drugs. Overall, we propose APE2 as a general regulator for the DDR pathway in genome integrity maintenance.

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Ataxia Telangiectasia Mutated Kinase Mediates NF-κB Serine 276 Phosphorylation and Interferon Expression via the IRF7-RIG-I Amplification Loop in Paramyxovirus Infection

Journal of Virology ◽

10.1128/jvi.02458-14 ◽

2014 ◽

Vol 89 (5) ◽

pp. 2628-2642 ◽

Cited By ~ 18

Author(s):

Ling Fang ◽

Sanjeev Choudhary ◽

Bing Tian ◽

Istvan Boldogh ◽

Chunying Yang ◽

...

Keyword(s):

Oxidative Stress ◽

Dna Damage ◽

Retinoic Acid ◽

Dna Damage Response ◽

Type I ◽

Regulatory Factor ◽

Ataxia Telangiectasia Mutated ◽

Damage Response ◽

Amplification Loop ◽

Inducible Gene

ABSTRACTRespiratory syncytial virus (RSV) is a primary etiological agent of childhood lower respiratory tract disease. Molecular patterns induced by active infection trigger a coordinated retinoic acid-inducible gene I (RIG-I)-Toll-like receptor (TLR) signaling response to induce inflammatory cytokines and antiviral mucosal interferons. Recently, we discovered a nuclear oxidative stress-sensitive pathway mediated by the DNA damage response protein, ataxia telangiectasia mutated (ATM), in cytokine-induced NF-κB/RelA Ser 276 phosphorylation. Here we observe that ATM silencing results in enhanced single-strand RNA (ssRNA) replication of RSVand Sendai virus, due to decreased expression and secretion of type I and III interferons (IFNs), despite maintenance of IFN regulatory factor 3 (IRF3)-dependent IFN-stimulated genes (ISGs). In addition to enhanced oxidative stress, RSV replication enhances foci of phosphorylated histone 2AX variant (γH2AX), Ser 1981 phosphorylation of ATM, and IKKγ/NEMO-dependent ATM nuclear export, indicating activation of the DNA damage response. ATM-deficient cells show defective RSV-induced mitogen and stress-activated kinase 1 (MSK-1) Ser 376 phosphorylation and reduced RelA Ser 276 phosphorylation, whose formation is required for IRF7 expression. We observe that RelA inducibly binds the native IFN regulatory factor 7 (IRF7) promoter in an ATM-dependent manner, and IRF7 inducibly binds to the endogenous retinoic acid-inducible gene I (RIG-I) promoter. Ectopic IRF7 expression restores RIG-I expression and type I/III IFN expression in ATM-silenced cells. We conclude that paramyxoviruses trigger the DNA damage response, a pathway required for MSK1 activation of phospho Ser 276 RelA formation to trigger the IRF7-RIG-I amplification loop necessary for mucosal IFN production. These data provide the molecular pathogenesis for defects in the cellular innate immunity of patients with homozygous ATM mutations.IMPORTANCERNA virus infections trigger cellular response pathways to limit spread to adjacent tissues. This “innate immune response” is mediated by germ line-encoded pattern recognition receptors that trigger activation of two, largely independent, intracellular NF-κB and IRF3 transcription factors. Downstream, expression of protective antiviral interferons is amplified by positive-feedback loops mediated by inducible interferon regulatory factors (IRFs) and retinoic acid inducible gene (RIG-I). Our results indicate that a nuclear oxidative stress- and DNA damage-sensing factor, ATM, is required to mediate a cross talk pathway between NF-κB and IRF7 through mediating phosphorylation of NF-κB. Our studies provide further information about the defects in cellular and innate immunity in patients with inherited ATM mutations.

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