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Article: Nucleic Acid sensors and type I interferon production in systemic lupus erythematosus.

Shrivastav, Meena / Niewold, Timothy B

2013 Volume 4, Page(s) 319

Abstract: The characteristic serologic feature of systemic lupus erythematosus (SLE) is autoantibodies against one's own nucleic acid or nucleic acid-binding proteins - DNA and RNA-binding nuclear proteins. Circulating autoantibodies can deposit in the tissue, ... ...

Abstract	The characteristic serologic feature of systemic lupus erythematosus (SLE) is autoantibodies against one's own nucleic acid or nucleic acid-binding proteins - DNA and RNA-binding nuclear proteins. Circulating autoantibodies can deposit in the tissue, causing inflammation and production of cytokines such as type 1 interferon (IFN). Investigations in human patients and animal models have implicated environmental as well as genetic factors in the biology of the SLE autoimmune response. Viral/Bacterial nucleic acid is a potent stimulant of innate immunity by both toll-like receptor (TLR) and non-TLR signaling cascades. Additionally, foreign DNA may act as an immunogen to drive an antigen-specific antibody response. Self nucleic acid is normally restricted to the nucleus or the mitochondria, away from the DNA/RNA sensors, and mechanisms exist to differentiate between foreign and self nucleic acid. In normal immunity, a diverse range of DNA and RNA sensors in different cell types form a dynamic and integrated molecular network to prevent viral infection. In SLE, pathologic activation of these sensors occurs via immune complexes consisting of autoantibodies bound to DNA or to nucleic acid-protein complexes. In this review, we will discuss recent studies outlining how mismanaged nucleic acid sensing networks promote autoimmunity and result in the over-production of type I IFN. This information is critical for improving therapeutic strategies for SLE disease.
Language	English
Publishing date	2013-10-07
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2013.00319
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Article ; Online: Regulation of DNA double-strand break repair pathway choice.

Shrivastav, Meena / De Haro, Leyma P / Nickoloff, Jac A

Cell research

2008 Volume 18, Issue 1, Page(s) 134–147

Abstract: DNA double-strand breaks (DSBs) are critical lesions that can result in cell death or a wide variety of genetic alterations including large- or small-scale deletions, loss of heterozygosity, translocations, and chromosome loss. DSBs are repaired by non- ... ...

Abstract	DNA double-strand breaks (DSBs) are critical lesions that can result in cell death or a wide variety of genetic alterations including large- or small-scale deletions, loss of heterozygosity, translocations, and chromosome loss. DSBs are repaired by non-homologous end-joining (NHEJ) and homologous recombination (HR), and defects in these pathways cause genome instability and promote tumorigenesis. DSBs arise from endogenous sources including reactive oxygen species generated during cellular metabolism, collapsed replication forks, and nucleases, and from exogenous sources including ionizing radiation and chemicals that directly or indirectly damage DNA and are commonly used in cancer therapy. The DSB repair pathways appear to compete for DSBs, but the balance between them differs widely among species, between different cell types of a single species, and during different cell cycle phases of a single cell type. Here we review the regulatory factors that regulate DSB repair by NHEJ and HR in yeast and higher eukaryotes. These factors include regulated expression and phosphorylation of repair proteins, chromatin modulation of repair factor accessibility, and the availability of homologous repair templates. While most DSB repair proteins appear to function exclusively in NHEJ or HR, a number of proteins influence both pathways, including the MRE11/RAD50/NBS1(XRS2) complex, BRCA1, histone H2AX, PARP-1, RAD18, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and ATM. DNA-PKcs plays a role in mammalian NHEJ, but it also influences HR through a complex regulatory network that may involve crosstalk with ATM, and the regulation of at least 12 proteins involved in HR that are phosphorylated by DNA-PKcs and/or ATM.
MeSH term(s)	Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle/genetics ; Cell Cycle/physiology ; Cell Cycle Proteins/physiology ; Chromosome Aberrations ; DNA Breaks, Double-Stranded ; DNA Repair/physiology ; DNA-Activated Protein Kinase/physiology ; DNA-Binding Proteins/physiology ; Eukaryotic Cells/metabolism ; Genomic Instability ; Humans ; Models, Biological ; Nuclear Proteins/physiology ; Protein-Serine-Threonine Kinases/physiology ; Recombination, Genetic/physiology ; Signal Transduction/genetics ; Species Specificity ; Tumor Suppressor Proteins/physiology ; Yeasts/genetics
Chemical Substances	Cell Cycle Proteins ; DNA-Binding Proteins ; Nuclear Proteins ; Tumor Suppressor Proteins ; ATM protein, human (EC 2.7.11.1) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; DNA-Activated Protein Kinase (EC 2.7.11.1) ; PRKDC protein, human (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2008-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1319303-x
ISSN	1748-7838 ; 1001-0602
ISSN (online)	1748-7838
ISSN	1001-0602
DOI	10.1038/cr.2007.111
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Zs.A 5283: Show issues

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Article ; Online: Chest Pain Risk Scores Can Reduce Emergent Cardiac Imaging Test Needs With Low Major Adverse Cardiac Events Occurrence in an Emergency Department Observation Unit.

Wang, Hao / Watson, Katherine / Robinson, Richard D / Domanski, Kristina H / Umejiego, Johnbosco / Hamblin, Layton / Overstreet, Sterling E / Akin, Amanda M / Hoang, Steven / Shrivastav, Meena / Collyer, Michael / Krech, Ryan N / Schrader, Chet D / Zenarosa, Nestor R

Critical pathways in cardiology

2016 Volume 15, Issue 4, Page(s) 145–151

Abstract: Objective: To compare and evaluate the performance of the HEART, Global Registry of Acute Coronary Events (GRACE), and Thrombolysis in Myocardial Infarction (TIMI) scores to predict major adverse cardiac event (MACE) rates after index placement in an ... ...

Abstract	Objective: To compare and evaluate the performance of the HEART, Global Registry of Acute Coronary Events (GRACE), and Thrombolysis in Myocardial Infarction (TIMI) scores to predict major adverse cardiac event (MACE) rates after index placement in an emergency department observation unit (EDOU) and to determine the need for observation unit initiation of emergent cardiac imaging tests, that is, noninvasive cardiac stress tests and invasive coronary angiography. Methods: A prospective observational single center study was conducted from January 2014 through June 2015. EDOU chest pain patients were included. HEART, GRACE, and TIMI scores were categorized as low (HEART ≤ 3, GRACE ≤ 108, and TIMI ≤1) versus elevated based on thresholds suggested in prior studies. Patients were followed for 6 months postdischarge. The results of emergent cardiac imaging tests, EDOU length of stay (LOS), and MACE occurrences were compared. Student t test was used to compare groups with continuous data, and χ testing was used for categorical data analysis. Results: Of 986 patients, emergent cardiac imaging tests were performed on 62%. A majority of patients were scored as low risk by all tools (85% by HEART, 81% by GRACE, and 80% by TIMI, P < 0.05). The low-risk patients had few abnormal cardiac imaging test results as compared with patients scored as intermediate to high risk (1% vs. 11% in HEART, 1% vs. 9% in TIMI, and 2% vs. 4% in GRACE, P < 0.05). The average LOS was 33 hours for patients with emergent cardiac imaging tests performed and 25 hours for patients without (P < 0.05). MACE occurrence rate demonstrated no significant difference regardless of whether tests were performed emergently (0.31% vs. 0.97% in HEART, 0.27% vs. 0.95% in TIMI, and 0% vs. 0.81% in GRACE, P > 0.05). Conclusions: Chest pain risk stratification via clinical decision tool scores can minimize the need for emergent cardiac imaging tests with less than 1% MACE occurrence, especially when the HEART score is used.
MeSH term(s)	Acute Coronary Syndrome/complications ; Acute Coronary Syndrome/diagnosis ; Acute Coronary Syndrome/epidemiology ; Chest Pain/diagnosis ; Chest Pain/epidemiology ; Chest Pain/etiology ; Coronary Angiography ; Diagnostic Imaging/utilization ; Electrocardiography ; Emergency Service, Hospital/statistics & numerical data ; Exercise Test ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Morbidity/trends ; Prognosis ; Prospective Studies ; ROC Curve ; Risk Assessment/methods ; Risk Factors ; Severity of Illness Index ; Texas/epidemiology ; Time Factors
Language	English
Publishing date	2016-12
Publishing country	United States
Document type	Journal Article ; Observational Study
ZDB-ID	2079676-6
ISSN	1535-2811 ; 1535-282X
ISSN (online)	1535-2811
ISSN	1535-282X
DOI	10.1097/HPC.0000000000000090
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Zs.A 5660: Show issues

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Article ; Online: ATM inhibitor KU-55933 increases the TMZ responsiveness of only inherently TMZ sensitive GBM cells.

Nadkarni, Aditi / Shrivastav, Meena / Mladek, Ann C / Schwingler, Paul M / Grogan, Patrick T / Chen, Junjie / Sarkaria, Jann N

Journal of neuro-oncology

2012 Volume 110, Issue 3, Page(s) 349–357

Abstract: Ataxia telangiectasia mutated (ATM) kinase is critical in sensing and repairing DNA double-stranded breaks (DSBs) such as those induced by temozolomide (TMZ). ATM deficiency increases TMZ sensitivity, which suggests that ATM inhibitors may be effective ... ...

Abstract	Ataxia telangiectasia mutated (ATM) kinase is critical in sensing and repairing DNA double-stranded breaks (DSBs) such as those induced by temozolomide (TMZ). ATM deficiency increases TMZ sensitivity, which suggests that ATM inhibitors may be effective TMZ sensitizing agents. In this study, the TMZ sensitizing effects of 2 ATM specific inhibitors were studied in established and xenograft-derived glioblastoma (GBM) lines that are inherently sensitive to TMZ and derivative TMZ-resistant lines. In parental U251 and U87 glioma lines, the addition of KU-55933 to TMZ significantly increased cell killing compared to TMZ alone [U251 survival: 0.004 ± 0.0015 vs. 0.08 ± 0.01 (p < 0.001), respectively, and U87 survival: 0.02 ± 0.005 vs. 0.04 ± 0.002 (p < 0.001), respectively] and also elevated the fraction of cells arrested in G2/M [U251 G2/M fraction: 61.8 ± 1.1 % vs. 35 ± 0.8 % (p < 0.001), respectively, and U87 G2/M fraction 25 ± 0.2 % vs.18.6 ± 0.4 % (p < 0.001), respectively]. In contrast, KU-55933 did not sensitize the resistant lines to TMZ, and neither TMZ alone or combined with KU-55933 induced a G2/M arrest. While KU-55933 did not enhance TMZ induced Chk1/Chk2 activation, it increased TMZ-induced residual γ-H2AX foci in the parental cells but not in the TMZ resistant cells. Similar sensitization was observed with either KU-55933 or CP-466722 combined with TMZ in GBM12 xenograft line but not in GBM12TMZ, which is resistant to TMZ due to MGMT overexpression. These findings are consistent with a model where ATM inhibition suppresses the repair of TMZ-induced DSBs in inherently TMZ-sensitive tumor lines, which suggests an ATM inhibitor potentially could be deployed with an improvement in the therapeutic window when combined with TMZ.
MeSH term(s)	Animals ; Antineoplastic Agents, Alkylating/pharmacology ; Apoptosis/drug effects ; Ataxia Telangiectasia Mutated Proteins ; Blotting, Western ; Brain Neoplasms/drug therapy ; Brain Neoplasms/metabolism ; Brain Neoplasms/pathology ; Cell Cycle Proteins/antagonists & inhibitors ; Cell Cycle Proteins/metabolism ; Cell Division/drug effects ; Cell Proliferation/drug effects ; DNA Damage/drug effects ; DNA-Binding Proteins/antagonists & inhibitors ; DNA-Binding Proteins/metabolism ; Dacarbazine/analogs & derivatives ; Dacarbazine/pharmacology ; Drug Resistance, Neoplasm/drug effects ; Flow Cytometry ; G2 Phase/drug effects ; Glioblastoma/drug therapy ; Glioblastoma/metabolism ; Glioblastoma/pathology ; Humans ; Immunoenzyme Techniques ; Mice ; Morpholines/pharmacology ; Neurons/drug effects ; Neurons/metabolism ; Neurons/pathology ; Protein-Serine-Threonine Kinases/antagonists & inhibitors ; Protein-Serine-Threonine Kinases/metabolism ; Pyrones/pharmacology ; Temozolomide ; Tumor Cells, Cultured ; Tumor Stem Cell Assay ; Tumor Suppressor Proteins/antagonists & inhibitors ; Tumor Suppressor Proteins/metabolism
Chemical Substances	2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one ; Antineoplastic Agents, Alkylating ; Cell Cycle Proteins ; DNA-Binding Proteins ; Morpholines ; Pyrones ; Tumor Suppressor Proteins ; Dacarbazine (7GR28W0FJI) ; ATM protein, human (EC 2.7.11.1) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; Atm protein, mouse (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Temozolomide (YF1K15M17Y)
Language	English
Publishing date	2012-10-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	604875-4
ISSN	1573-7373 ; 0167-594X
ISSN (online)	1573-7373
ISSN	0167-594X
DOI	10.1007/s11060-012-0979-0
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Zs.A 1825: Show issues

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Article ; Online: DNA-PK phosphorylation of RPA32 Ser4/Ser8 regulates replication stress checkpoint activation, fork restart, homologous recombination and mitotic catastrophe.

Ashley, Amanda K / Shrivastav, Meena / Nie, Jingyi / Amerin, Courtney / Troksa, Kyle / Glanzer, Jason G / Liu, Shengqin / Opiyo, Stephen O / Dimitrova, Diana D / Le, Phuong / Sishc, Brock / Bailey, Susan M / Oakley, Greg G / Nickoloff, Jac A

DNA repair

2014 Volume 21, Page(s) 131–139

Abstract: Genotoxins and other factors cause replication stress that activate the DNA damage response (DDR), comprising checkpoint and repair systems. The DDR suppresses cancer by promoting genome stability, and it regulates tumor resistance to chemo- and ... ...

Abstract	Genotoxins and other factors cause replication stress that activate the DNA damage response (DDR), comprising checkpoint and repair systems. The DDR suppresses cancer by promoting genome stability, and it regulates tumor resistance to chemo- and radiotherapy. Three members of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, ATM, ATR, and DNA-PK, are important DDR proteins. A key PIKK target is replication protein A (RPA), which binds single-stranded DNA and functions in DNA replication, DNA repair, and checkpoint signaling. An early response to replication stress is ATR activation, which occurs when RPA accumulates on ssDNA. Activated ATR phosphorylates many targets, including the RPA32 subunit of RPA, leading to Chk1 activation and replication arrest. DNA-PK also phosphorylates RPA32 in response to replication stress, and we demonstrate that cells with DNA-PK defects, or lacking RPA32 Ser4/Ser8 targeted by DNA-PK, confer similar phenotypes, including defective replication checkpoint arrest, hyper-recombination, premature replication fork restart, failure to block late origin firing, and increased mitotic catastrophe. We present evidence that hyper-recombination in these mutants is ATM-dependent, but the other defects are ATM-independent. These results indicate that DNA-PK and ATR signaling through RPA32 plays a critical role in promoting genome stability and cell survival in response to replication stress.
MeSH term(s)	Animals ; Ataxia Telangiectasia Mutated Proteins/genetics ; Ataxia Telangiectasia Mutated Proteins/metabolism ; CHO Cells ; Cell Line, Tumor ; Checkpoint Kinase 1 ; Cricetinae ; Cricetulus ; DNA Replication ; DNA-Activated Protein Kinase/genetics ; DNA-Activated Protein Kinase/metabolism ; G2 Phase Cell Cycle Checkpoints ; Homologous Recombination ; Humans ; Mutation ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Phosphorylation ; Protein Kinases/genetics ; Protein Kinases/metabolism ; Replication Protein A/genetics ; Replication Protein A/metabolism ; Serine/genetics ; Serine/metabolism
Chemical Substances	Nuclear Proteins ; Replication Protein A ; Serine (452VLY9402) ; Protein Kinases (EC 2.7.-) ; ATM protein, human (EC 2.7.11.1) ; ATR protein, human (EC 2.7.11.1) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; CHEK1 protein, human (EC 2.7.11.1) ; Checkpoint Kinase 1 (EC 2.7.11.1) ; DNA-Activated Protein Kinase (EC 2.7.11.1) ; PRKDC protein, human (EC 2.7.11.1) ; RPA2 protein, human (EC 2.7.7.7)
Language	English
Publishing date	2014-05-10
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2071608-4
ISSN	1568-7856 ; 1568-7864
ISSN (online)	1568-7856
ISSN	1568-7864
DOI	10.1016/j.dnarep.2014.04.008
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Zs.A 5555: Show issues

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Article: Enhanced gamma-glutamylcysteine synthetase activity decreases drug-induced oxidative stress levels and cytotoxicity.

Das, Gokul C / Bacsi, Attila / Shrivastav, Meena / Hazra, Tapas K / Boldogh, Istvan

Molecular carcinogenesis

2006 Volume 45, Issue 9, Page(s) 635–647

Abstract: Multidrug resistance of cancer cells can be intrinsic or acquired and occurs due to various reasons, including increased repair of genotoxic damage, an enhanced ability to remove/detoxify chemical agents, or reactive oxygen species (ROS), and repression ... ...

Abstract	Multidrug resistance of cancer cells can be intrinsic or acquired and occurs due to various reasons, including increased repair of genotoxic damage, an enhanced ability to remove/detoxify chemical agents, or reactive oxygen species (ROS), and repression of apoptosis. Human A2780/100 ovarian carcinoma cells exhibit resistance to DNA cross-linking agents, chlorambucil (Cbl), cisplatin (Cpl), melphalan (Mel), and ionizing radiation (IR) compared to the parental cell line, A2780. In the present study, we show that when A2780/100 and A2780 cells were treated with Cbl, GSH was extruded via methionine or cystathionine-inhibitable transporters of intact plasma membrane. GSH loss was followed by a rapid increase in ROS levels. The resistant, but not drug-sensitive cells normalized the intracellular GSH concentration along with ROS levels within 4-6 h after Cbl addition, and survived drug treatment. Normalization of GSH and ROS levels in A2780/100 cells correlated well with elevated gamma-glutamylcysteine synthetase (gamma-GCS) activity (10 +/- 1.8-fold over A2780 cells). Ectopic overexpression of the gamma-GCS heavy subunit in drug-sensitive cells nearly restored GSH and ROS to pre-treatment levels consequently increased cellular resistance to genotoxic agents (Cbl, Cpl, and IR), while overexpression of gamma-GCS light subunit had no such effects. Thus, in our model system, drug-resistant cells have the inherent ability to maintain increased gamma-GCS activity, reestablish physiological GSH, and cellular redox state and maintain increased cellular resistance to DNA cross-linking agents and IR.
MeSH term(s)	Carcinoma/enzymology ; Carcinoma/genetics ; Cell Membrane/metabolism ; Cisplatin/toxicity ; Cross-Linking Reagents/toxicity ; Drug Resistance, Multiple/genetics ; Drug Resistance, Neoplasm/genetics ; Female ; Glutamate-Cysteine Ligase/genetics ; Glutamate-Cysteine Ligase/metabolism ; Glutathione/metabolism ; Humans ; Ovarian Neoplasms/enzymology ; Ovarian Neoplasms/genetics ; Oxidation-Reduction ; Oxidative Stress/genetics ; Reactive Oxygen Species/metabolism ; Transcriptional Activation ; Tumor Cells, Cultured
Chemical Substances	Cross-Linking Reagents ; Reactive Oxygen Species ; Glutamate-Cysteine Ligase (EC 6.3.2.2) ; Glutathione (GAN16C9B8O) ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2006-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1004029-8
ISSN	1098-2744 ; 0899-1987
ISSN (online)	1098-2744
ISSN	0899-1987
DOI	10.1002/mc.20184
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Zs.A 2664: Show issues

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Article ; Online: DNA-PKcs and ATM co-regulate DNA double-strand break repair.

Shrivastav, Meena / Miller, Cheryl A / De Haro, Leyma P / Durant, Stephen T / Chen, Benjamin P C / Chen, David J / Nickoloff, Jac A

DNA repair

2009 Volume 8, Issue 8, Page(s) 920–929

Abstract: DNA double-strand breaks (DSBs) are repaired by nonhomologous end-joining (NHEJ) and homologous recombination (HR). The NHEJ/HR decision is under complex regulation and involves DNA-dependent protein kinase (DNA-PKcs). HR is elevated in DNA-PKcs null ... ...

Abstract	DNA double-strand breaks (DSBs) are repaired by nonhomologous end-joining (NHEJ) and homologous recombination (HR). The NHEJ/HR decision is under complex regulation and involves DNA-dependent protein kinase (DNA-PKcs). HR is elevated in DNA-PKcs null cells, but suppressed by DNA-PKcs kinase inhibitors, suggesting that kinase-inactive DNA-PKcs (DNA-PKcs-KR) would suppress HR. Here we use a direct repeat assay to monitor HR repair of DSBs induced by I-SceI nuclease. Surprisingly, DSB-induced HR in DNA-PKcs-KR cells was 2- to 3-fold above the elevated HR level of DNA-PKcs null cells, and approximately 4- to 7-fold above cells expressing wild-type DNA-PKcs. The hyperrecombination in DNA-PKcs-KR cells compared to DNA-PKcs null cells was also apparent as increased resistance to DNA crosslinks induced by mitomycin C. ATM phosphorylates many HR proteins, and ATM is expressed at a low level in cells lacking DNA-PKcs, but restored to wild-type level in cells expressing DNA-PKcs-KR. Several clusters of phosphorylation sites in DNA-PKcs, including the T2609 cluster, which is phosphorylated by DNA-PKcs and ATM, regulate access of repair factors to broken ends. Our results indicate that ATM-dependent phosphorylation of DNA-PKcs-KR contributes to the hyperrecombination phenotype. Interestingly, DNA-PKcs null cells showed more persistent ionizing radiation-induced RAD51 foci (but lower HR levels) compared to DNA-PKcs-KR cells, consistent with HR completion requiring RAD51 turnover. ATM may promote RAD51 turnover, suggesting a second (not mutually exclusive) mechanism by which restored ATM contributes to hyperrecombination in DNA-PKcs-KR cells. We propose a model in which DNA-PKcs and ATM coordinately regulate DSB repair by NHEJ and HR.
MeSH term(s)	Animals ; Ataxia Telangiectasia Mutated Proteins ; CHO Cells ; Cell Cycle Proteins/antagonists & inhibitors ; Cell Cycle Proteins/metabolism ; Cricetinae ; Cricetulus ; DNA Breaks, Double-Stranded/radiation effects ; DNA Damage ; DNA Repair/radiation effects ; DNA-Activated Protein Kinase/metabolism ; DNA-Binding Proteins/antagonists & inhibitors ; DNA-Binding Proteins/metabolism ; Enzyme Activation/radiation effects ; Models, Biological ; Mutation/genetics ; Phosphorylation/radiation effects ; Phosphothreonine/metabolism ; Protein-Serine-Threonine Kinases/antagonists & inhibitors ; Protein-Serine-Threonine Kinases/metabolism ; Rad51 Recombinase/metabolism ; Radiation, Ionizing ; Recombination, Genetic/genetics ; Tumor Suppressor Proteins/antagonists & inhibitors ; Tumor Suppressor Proteins/metabolism
Chemical Substances	Cell Cycle Proteins ; DNA-Binding Proteins ; Tumor Suppressor Proteins ; Phosphothreonine (1114-81-4) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; DNA-Activated Protein Kinase (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Rad51 Recombinase (EC 2.7.7.-)
Language	English
Publishing date	2009-06-16
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2071608-4
ISSN	1568-7856 ; 1568-7864
ISSN (online)	1568-7856
ISSN	1568-7864
DOI	10.1016/j.dnarep.2009.05.006
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Article ; Online: Distinct roles for DNA-PK, ATM and ATR in RPA phosphorylation and checkpoint activation in response to replication stress.

Liu, Shengqin / Opiyo, Stephen O / Manthey, Karoline / Glanzer, Jason G / Ashley, Amanda K / Amerin, Courtney / Troksa, Kyle / Shrivastav, Meena / Nickoloff, Jac A / Oakley, Greg G

Nucleic acids research

2012 Volume 40, Issue 21, Page(s) 10780–10794

Abstract: DNA damage encountered by DNA replication forks poses risks of genome destabilization, a precursor to carcinogenesis. Damage checkpoint systems cause cell cycle arrest, promote repair and induce programed cell death when damage is severe. Checkpoints are ...

Abstract	DNA damage encountered by DNA replication forks poses risks of genome destabilization, a precursor to carcinogenesis. Damage checkpoint systems cause cell cycle arrest, promote repair and induce programed cell death when damage is severe. Checkpoints are critical parts of the DNA damage response network that act to suppress cancer. DNA damage and perturbation of replication machinery causes replication stress, characterized by accumulation of single-stranded DNA bound by replication protein A (RPA), which triggers activation of ataxia telangiectasia and Rad3 related (ATR) and phosphorylation of the RPA32, subunit of RPA, leading to Chk1 activation and arrest. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) [a kinase related to ataxia telangiectasia mutated (ATM) and ATR] has well characterized roles in DNA double-strand break repair, but poorly understood roles in replication stress-induced RPA phosphorylation. We show that DNA-PKcs mutant cells fail to arrest replication following stress, and mutations in RPA32 phosphorylation sites targeted by DNA-PKcs increase the proportion of cells in mitosis, impair ATR signaling to Chk1 and confer a G2/M arrest defect. Inhibition of ATR and DNA-PK (but not ATM), mimic the defects observed in cells expressing mutant RPA32. Cells expressing mutant RPA32 or DNA-PKcs show sustained H2AX phosphorylation in response to replication stress that persists in cells entering mitosis, indicating inappropriate mitotic entry with unrepaired damage.
MeSH term(s)	Animals ; Ataxia Telangiectasia Mutated Proteins ; CHO Cells ; Cell Cycle Checkpoints ; Cell Cycle Proteins/metabolism ; Checkpoint Kinase 1 ; Cricetinae ; Cricetulus ; DNA Breaks, Double-Stranded ; DNA Repair ; DNA Replication ; DNA-Activated Protein Kinase/metabolism ; DNA-Binding Proteins/metabolism ; Humans ; Mitosis ; Mutation ; Phosphorylation ; Protein Kinases/metabolism ; Protein-Serine-Threonine Kinases/metabolism ; Replication Protein A/chemistry ; Replication Protein A/genetics ; Replication Protein A/metabolism ; Serine/metabolism ; Signal Transduction ; Stress, Physiological ; Tumor Suppressor Proteins/metabolism
Chemical Substances	Cell Cycle Proteins ; DNA-Binding Proteins ; Replication Protein A ; Tumor Suppressor Proteins ; Serine (452VLY9402) ; Protein Kinases (EC 2.7.-) ; ATM protein, human (EC 2.7.11.1) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; CHEK1 protein, human (EC 2.7.11.1) ; Checkpoint Kinase 1 (EC 2.7.11.1) ; DNA-Activated Protein Kinase (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2012-09-12
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gks849
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Article: Aberrant methylation of the ATM promoter correlates with increased radiosensitivity in a human colorectal tumor cell line.

Kim, Wan-ju / Vo, Quynh N / Shrivastav, Meena / Lataxes, Tamara A / Brown, Kevin D

Oncogene

2002 Volume 21, Issue 24, Page(s) 3864–3871

Abstract: Recent findings suggest that DNA alkylating agents trigger cellular responses that overlap those activated after ionizing radiation. Moreover, activation of these responses is dependent upon a functional mismatch repair (MMR) system. These developments ... ...

Abstract	Recent findings suggest that DNA alkylating agents trigger cellular responses that overlap those activated after ionizing radiation. Moreover, activation of these responses is dependent upon a functional mismatch repair (MMR) system. These developments led us to test if MMR-deficient cells may be compromised in their ability to activate appropriate cellular signaling pathways after ionizing radiation. An initial experiment to address this notion was to determine the level of radiosensitivity of several MMR-deficient cell lines derived from patients with Hereditary Non-Polyposis Colorectal Cancer (HNPCC). While two of the three HNPCC lines investigated show levels of radiosensitivity consistent with that displayed by normal human fibroblasts, HCT-116 cells display moderate radiosensitivity compared to the other MMR-deficient lines. This increased sensitivity to ionizing radiation correlates with lowered levels of ATM expression in HCT-116. Analysis of genomic DNA from HCT-116 cells determined that these cells possess aberrant methylation of multiple CpG dinucleotides within the proximal promoter region of the ATM gene. The significance of this finding is underscored by our observations that co-culturing HCT-116 cells with the DNA demethylating agent 5-azacytidine reverses promoter methylation, promotes normal levels of ATM expression, and restores normal radiosensitivity. The proximal ATM promoter is a approximately 520 bp region shared with the NPAT gene, and current evidence suggests that this region functions as a bi-directional promoter. We found that, unlike ATM, the methylation status of this intergenic region does not effect the expression of the NPAT gene. In sum, these observations indicate that the ATM gene is a novel target for epigentic silencing through inappropriate methylation of its proximal promoter region.
MeSH term(s)	Ataxia Telangiectasia Mutated Proteins ; Azacitidine/pharmacology ; Cell Cycle Proteins ; Cell Line ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/metabolism ; Colorectal Neoplasms/radiotherapy ; CpG Islands ; DNA Methylation ; DNA Primers/pharmacology ; DNA-Binding Proteins ; Dose-Response Relationship, Radiation ; Electrophoresis, Polyacrylamide Gel ; Enzyme Inhibitors/pharmacology ; Humans ; Microscopy, Fluorescence ; Models, Genetic ; Promoter Regions, Genetic ; Protein-Serine-Threonine Kinases/genetics ; Tumor Cells, Cultured ; Tumor Suppressor Proteins ; Up-Regulation
Chemical Substances	Cell Cycle Proteins ; DNA Primers ; DNA-Binding Proteins ; Enzyme Inhibitors ; Tumor Suppressor Proteins ; ATM protein, human (EC 2.7.11.1) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Azacitidine (M801H13NRU)
Language	English
Publishing date	2002-05-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639046-8
ISSN	1476-5594 ; 0950-9232
ISSN (online)	1476-5594
ISSN	0950-9232
DOI	10.1038/sj.onc.1205485
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Article: UV radiation induces delayed hyperrecombination associated with hypermutation in human cells.

Durant, Stephen T / Paffett, Kimberly S / Shrivastav, Meena / Timmins, Graham S / Morgan, William F / Nickoloff, Jac A

Molecular and cellular biology

2006 Volume 26, Issue 16, Page(s) 6047–6055

Abstract: Ionizing radiation induces delayed genomic instability in human cells, including chromosomal abnormalities and hyperrecombination. Here, we investigate delayed genome instability of cells exposed to UV radiation. We examined homologous recombination- ... ...

Abstract	Ionizing radiation induces delayed genomic instability in human cells, including chromosomal abnormalities and hyperrecombination. Here, we investigate delayed genome instability of cells exposed to UV radiation. We examined homologous recombination-mediated reactivation of a green fluorescent protein (GFP) gene in p53-proficient human cells. We observed an approximately 5-fold enhancement of delayed hyperrecombination (DHR) among cells surviving a low dose of UV-C (5 J/m2), revealed as mixed GFP+/- colonies. UV-B did not induce DHR at an equitoxic (75 J/m2) dose or a higher dose (150 J/m2). UV is known to induce delayed hypermutation associated with increased oxidative stress. We found that hypoxanthine phosphoribosyltransferase (HPRT) mutation frequencies were approximately 5-fold higher in strains derived from GFP+/- (DHR) colonies than in strains in which recombination was directly induced by UV (GFP+ colonies). To determine whether hypermutation was directly caused by hyperrecombination, we analyzed hprt mutation spectra. Large-scale alterations reflecting large deletions and insertions were observed in 25% of GFP+ strains, and most mutants had a single change in HPRT. In striking contrast, all mutations arising in the hypermutable GFP+/- strains were small (1- to 2-base) changes, including substitutions, deletions, and insertions (reminiscent of mutagenesis from oxidative damage), and the majority were compound, with an average of four hprt mutations per mutant. The absence of large hprt deletions in DHR strains indicates that DHR does not cause hypermutation. We propose that UV-induced DHR and hypermutation result from a common source, namely, increased oxidative stress. These two forms of delayed genome instability may collaborate in skin cancer initiation and progression.
MeSH term(s)	Cell Death/radiation effects ; Cell Survival/radiation effects ; Exons/genetics ; Green Fluorescent Proteins/metabolism ; Humans ; Hypoxanthine Phosphoribosyltransferase/genetics ; Models, Biological ; Mutagenesis/genetics ; Mutagenesis/radiation effects ; Point Mutation/genetics ; Recombination, Genetic/genetics ; Recombination, Genetic/radiation effects ; Tumor Cells, Cultured ; Ultraviolet Rays
Chemical Substances	Green Fluorescent Proteins (147336-22-9) ; Hypoxanthine Phosphoribosyltransferase (EC 2.4.2.8)
Language	English
Publishing date	2006-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.00444-06
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