Parvovirus B19 Nonstructural Protein-Induced Damage of Cellular DNA and Resultant Apoptosis

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Parvovirus B19 is a widespread virus with diverse clinical presentations. The viral nonstructural protein, NS1, binds to and cleaves the viral genome, and induces apoptosis when transfected into nonpermissive cells, such as hepatocytes. We hypothesized that the cytotoxicity of NS1 in such cells results from chromosomal DNA damage caused by the DNA-nicking and DNA-attaching activities of NS1. Upon testing this hypothesis, we found that NS1 covalently binds to cellular DNA and is modified by PARP, an enzyme involved in repairing single-stranded DNA nicks. We furthermore discovered that the DNA nick repair pathway initiated by poly(ADPribose)polymerase and the DNA repair pathways initiated by ATM/ATR are necessary for efficient apoptosis resulting from NS1 expression.

Related collections

Most cited references 59

Record: found
Abstract: found
Article: not found

ATM and related protein kinases: safeguarding genome integrity.

Yosef Shiloh (2003)

Maintenance of genome stability is essential for avoiding the passage to neoplasia. The DNA-damage response--a cornerstone of genome stability--occurs by a swift transduction of the DNA-damage signal to many cellular pathways. A prime example is the cellular response to DNA double-strand breaks, which activate the ATM protein kinase that, in turn, modulates numerous signalling pathways. ATM mutations lead to the cancer-predisposing genetic disorder ataxia-telangiectasia (A-T). Understanding ATM's mode of action provides new insights into the association between defective responses to DNA damage and cancer, and brings us closer to resolving the issue of cancer predisposition in some A-T carriers.

0 comments Cited 497 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor.

Seong-Woon Yu, Hongmin Wang, Marc F Poitras … (2002)

Poly(ADP-ribose) polymerase-1 (PARP-1) protects the genome by functioning in the DNA damage surveillance network. PARP-1 is also a mediator of cell death after ischemia-reperfusion injury, glutamate excitotoxicity, and various inflammatory processes. We show that PARP-1 activation is required for translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus and that AIF is necessary for PARP-1-dependent cell death. N-methyl-N'-nitro-N-nitrosoguanidine, H2O2, and N-methyl-d-aspartate induce AIF translocation and cell death, which is prevented by PARP inhibitors or genetic knockout of PARP-1, but is caspase independent. Microinjection of an antibody to AIF protects against PARP-1-dependent cytotoxicity. These data support a model in which PARP-1 activation signals AIF release from mitochondria, resulting in a caspase-independent pathway of programmed cell death.

0 comments Cited 339 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine.

J Sarkaria, E Busby, R. S. Tibbetts … (1999)

Caffeine exposure sensitizes tumor cells to ionizing radiation and other genotoxic agents. The radiosensitizing effects of caffeine are associated with the disruption of multiple DNA damage-responsive cell cycle checkpoints. The similarity of these checkpoint defects to those seen in ataxia-telangiectasia (A-T) suggested that caffeine might inhibit one or more components in an A-T mutated (ATM)-dependent checkpoint pathway in DNA-damaged cells. We now show that caffeine inhibits the catalytic activity of both ATM and the related kinase, ATM and Rad3-related (ATR), at drug concentrations similar to those that induce radiosensitization. Moreover, like ATM-deficient cells, caffeine-treated A549 lung carcinoma cells irradiated in G2 fail to arrest progression into mitosis, and S-phase-irradiated cells exhibit radioresistant DNA synthesis. Similar concentrations of caffeine also inhibit gamma- and UV radiation-induced phosphorylation of p53 on Ser15, a modification that may be directly mediated by the ATM and ATR kinases. DNA-dependent protein kinase, another ATM-related protein involved in DNA damage repair, was resistant to the inhibitory effects of caffeine. Likewise, the catalytic activity of the G2 checkpoint kinase, hChk1, was only marginally suppressed by caffeine but was inhibited potently by the structurally distinct radiosensitizer, UCN-01. These data suggest that the radiosensitizing effects of caffeine are related to inhibition of the protein kinase activities of ATM and ATR and that both proteins are relevant targets for the development of novel anticancer agents.

0 comments Cited 169 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): Int J Med Sci

Journal ID (publisher-id): ijms

Title: International Journal of Medical Sciences

Publisher: Ivyspring International Publisher (Sydney )

ISSN (Electronic): 1449-1907

Publication date Collection: 2011

Publication date (Electronic): 15 January 2011

Volume: 8

Issue: 2

Pages: 88-96

Affiliations

1. Huck Institute for Life Sciences, Pennsylvania State University College of Medicine/Milton S. Hershey Medical Center, Hershey, PA, USA

2. Current: Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, USA

3. MD/PhD Program, Pennsylvania State University College of Medicine/Milton S. Hershey Medical Center, Hershey, PA, USA

4. Chemical Biology Division, Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä, Finland

5. Division of Rheumatology, Department of Medicine, Pennsylvania State University College of Medicine/Milton S. Hershey Medical Center, Hershey, PA, USA

6. Current: Quest Diagnostics Nichols Institute, San Juan Capistrano, CA, USA

Author notes

✉ Corresponding author: Stanley J. Naides, MD, Immunology, Quest Diagnostics Nichols Institute, 33608 Ortega Highway, San Juan Capistrano, CA 92690. Tel. 949 728-4578; fax 949 728-7852; email: stanley.j.naides@ 123456questdiagnostics.com

Conflict of Interest: The authors have declared that no conflict of interest exists.

Article

Publisher ID: ijmsv08p0088

DOI: 10.7150/ijms.8.88

PMC ID: 3030141

PubMed ID: 21278893

SO-VID: ecfb0214-e08a-44b5-a8cf-055c8586949c

Copyright © © Ivyspring International Publisher. All rights reserved. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited.

Parvovirus B19 Nonstructural Protein-Induced Damage of Cellular DNA and Resultant Apoptosis

Read this article at

Abstract

Related collections

Genome Integrity

Most cited references 59

ATM and related protein kinases: safeguarding genome integrity.

Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor.

Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine.

Author and article information

Journal

Affiliations

Author notes

Article

History

Categories

Comments

Comment on this article

Similar content 385

Cited by 7

Most referenced authors 869