| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Molecular Biology and Genetics |
Division of Applied Toxicology, Institute of Toxicology, University of Mainz, D-55131 Mainz, Germany [K. O., B. K.]; and Laboratory of Structural Biology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709-2233 [R. W. S., S. H. W.]
DNA polymerase ß (ß-pol), which is involved in base excision repair, was investigated for its role in protection of cells against various genotoxic agents and cytostatic drugs using ß-pol knockout mouse fibroblasts. We show that cells lacking ß-pol are highly sensitive to induction of apoptosis and chromosomal breakage by methylating agents, such as N-methyl-N'-nitro-N-nitrosoguanidine and methyl methanesulfonate and the cross-linking antineoplastic drugs mitomycin C and mafosfamide. The cross-sensitivity between the agents observed suggests that ß-pol is involved in repair not only of DNA methylation lesions but also of other kinds of DNA damage induced by various cytostatic drugs. Cells deficient in ß-pol were not hypersensitive to cisplatin, melphalan, benzo(a)pyrene diol epoxide, chloroethylnitrosourea, or UV light. Because both established and primary ß-pol knockout fibroblasts displayed the hypersensitive phenotype, which, moreover, was complemented by transfection with a ß-pol expression vector, the alkylating agent hypersensitivity can clearly be attributed to the ß-pol deficiency. The results demonstrate that ß-pol-driven base excision repair is highly important for protection of cells against cell killing due to apoptosis and induced chromosomal breakage and suggest that incompletely repaired DNA damage causes chromosomal changes and may act as a trigger of DNA damage-induced apoptosis.
This article has been cited by other articles:
|
|
 |
|
  C. N. Kundu, R. Balusu, A. S. Jaiswal, and S. Narayan Adenomatous polyposis coli-mediated hypersensitivity of mouse embryonic fibroblast cell lines to methylmethane sulfonate treatment: implication of base excision repair pathways Carcinogenesis, October 1, 2007; 28(10): 2089 - 2095. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Sarnowska, E. A. Grzybowska, K. Sobczak, R. Konopinski, A. Wilczynska, M. Szwarc, T. J. Sarnowski, W. J. Krzyzosiak, and J. A. Siedlecki Hairpin structure within the 3'UTR of DNA polymerase {beta} mRNA acts as a post-transcriptional regulatory element and interacts with Hax-1 Nucleic Acids Res., August 17, 2007; (2007) gkm502v1. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Wang, N. Bhattacharyya, T. Rabi, L. Wang, and S. Banerjee Mammary carcinogenesis in transgenic mice expressing a dominant-negative mutant of DNA polymerase {beta} in their mammary glands Carcinogenesis, June 1, 2007; 28(6): 1356 - 1363. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Starcevic, S. Dalal, J. Jaeger, and J. B. Sweasy The Hydrophobic Hinge Region of Rat DNA Polymerase {beta} Is Critical for Substrate Binding Pocket Geometry J. Biol. Chem., August 5, 2005; 280(31): 28388 - 28393. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Pascucci, M. T. Russo, M. Crescenzi, M. Bignami, and E. Dogliotti The accumulation of MMS-induced single strand breaks in G1 phase is recombinogenic in DNA polymerase {beta} defective mammalian cells Nucleic Acids Res., January 12, 2005; 33(1): 280 - 288. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Wang, N. Bhattacharyya, D. M. Chelsea, P. F. Escobar, and S. Banerjee A Novel Nuclear Protein, MGC5306 Interacts with DNA Polymerase {beta} and Has a Potential Role in Cellular Phenotype Cancer Res., November 1, 2004; 64(21): 7673 - 7677. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Fotiadou, O. Henegariu, and J. B. Sweasy DNA Polymerase {beta} Interacts with TRF2 and Induces Telomere Dysfunction in a Murine Mammary Cell Line Cancer Res., June 1, 2004; 64(11): 3830 - 3837. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Li, S. H. Berger, and M. D. Wyatt Involvement of base excision repair in response to therapy targeted at thymidylate synthase Mol. Cancer Ther., June 1, 2004; 3(6): 747 - 753. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. De Bont and N. van Larebeke Endogenous DNA damage in humans: a review of quantitative data Mutagenesis, May 1, 2004; 19(3): 169 - 185. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Morales-Ramirez, T. Vallarino-Kelly, V. L. Cruz-Vallejo, R. Lopez-Iturbe, and H. Alvaro-Delgadillo In vivo kinetics of micronuclei induction by bifunctional alkylating antineoplastics Mutagenesis, May 1, 2004; 19(3): 207 - 213. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-R. Lee, S.-H. Kim, H.-J. Cho, K.-Y. Lee, A. R. Moon, H. G. Jeong, J.-S. Lee, J.-W. Hyun, M.-H. Chung, and H. J. You Transcription Factors NF-YA Regulate the Induction of Human OGG1 Following DNA-alkylating Agent Methylmethane Sulfonate (MMS) Treatment J. Biol. Chem., March 12, 2004; 279(11): 9857 - 9866. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. F. El-Khamisy, M. Masutani, H. Suzuki, and K. W. Caldecott A requirement for PARP-1 for the assembly or stability of XRCC1 nuclear foci at sites of oxidative DNA damage Nucleic Acids Res., October 1, 2003; 31(19): 5526 - 5533. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Kelley, Y. W. Kow, and D. M. Wilson III Disparity between DNA Base Excision Repair in Yeast and Mammals: Translational Implications Cancer Res., February 1, 2003; 63(3): 549 - 554. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. S. Kedar, S.-J. Kim, A. Robertson, E. Hou, R. Prasad, J. K. Horton, and S. H. Wilson Direct Interaction between Mammalian DNA Polymerase beta and Proliferating Cell Nuclear Antigen J. Biol. Chem., August 16, 2002; 277(34): 31115 - 31123. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Vens, E. Dahmen-Mooren, M. Verwijs-Janssen, W. Blyweert, L. Graversen, H. Bartelink, and A. C. Begg The role of DNA polymerase {beta} in determining sensitivity to ionizing radiation in human tumor cells Nucleic Acids Res., July 1, 2002; 30(13): 2995 - 3004. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. E. Thompson, P. K. Rogan, J. I. Risinger, and J. A. Taylor Splice Variants but not Mutations of DNA Polymerase {beta} Are Common in Bladder Cancer Cancer Res., June 1, 2002; 62(11): 3251 - 3256. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. W. Sobol, D. E. Watson, J. Nakamura, F. M. Yakes, E. Hou, J. K. Horton, J. Ladapo, B. Van Houten, J. A. Swenberg, K. R. Tindall, et al. Mutations associated with base excision repair deficiency and methylation-induced genotoxic stress PNAS, May 14, 2002; 99(10): 6860 - 6865. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Taylor, A. Thistlethwaite, and K. W. Caldecott Central Role for the XRCC1 BRCT I Domain in Mammalian DNA Single-Strand Break Repair Mol. Cell. Biol., April 15, 2002; 22(8): 2556 - 2563. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kobayashi, M. Watanabe, Y. Okada, H. Sawa, H. Takai, M. Nakanishi, Y. Kawase, H. Suzuki, K. Nagashima, K. Ikeda, et al. Hydrocephalus, Situs Inversus, Chronic Sinusitis, and Male Infertility in DNA Polymerase {lambda}-Deficient Mice: Possible Implication for the Pathogenesis of Immotile Cilia Syndrome Mol. Cell. Biol., April 15, 2002; 22(8): 2769 - 2776. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ochs, J. Lips, S. Profittlich, and B. Kaina Deficiency in DNA Polymerase {beta} Provokes Replication-dependent Apoptosis via DNA Breakage, Bcl-2 Decline and Caspase-3/9 Activation Cancer Res., March 1, 2002; 62(5): 1524 - 1530. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. T. Tomicic, R. Thust, R. W. Sobol, and B. Kaina DNA Polymerase {beta} Mediates Protection of Mammalian Cells against Ganciclovir-induced Cytotoxicity and DNA Breakage Cancer Res., October 1, 2001; 61(20): 7399 - 7403. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kobune, Y. Xu, C. Baum, M. R. Kelley, and D. A. Williams Retrovirus-mediated Expression of the Base Excision Repair Proteins, Formamidopyrimidine DNA Glycosylase or Human Oxoguanine DNA Glycosylase, Protects Hematopoietic Cells from N,N',N''-Triethylenethiophosphoramide (thioTEPA)-induced Toxicity in Vitro and in Vivo Cancer Res., July 1, 2001; 61(13): 5116 - 5125. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Lackinger, U. Eichhorn, and B. Kaina Effect of ultraviolet light, methyl methanesulfonate and ionizing radiation on the genotoxic response and apoptosis of mouse fibroblasts lacking c-Fos, p53 or both Mutagenesis, May 1, 2001; 16(3): 233 - 241. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Lips and B. Kaina DNA double-strand breaks trigger apoptosis in p53-deficient fibroblasts Carcinogenesis, April 1, 2001; 22(4): 579 - 585. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ochs and B. Kaina Apoptosis Induced by DNA Damage O -Methylguanine Is Bcl-2 and Caspase-9/3 Regulated and Fas/Caspase-8 Independent Cancer Res., October 1, 2000; 60(20): 5815 - 5824. [Abstract] [Full Text]
|
|
|
|
|
|
P. Fortini, B. Pascucci, F. Belisario, and E. Dogliotti DNA polymerase {beta} is required for efficient DNA strand break repair induced by methyl methanesulfonate but not by hydrogen peroxide Nucleic Acids Res., August 15, 2000; 28(16): 3040 - 3046. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Parra, F. Lluis, F. Miralles, C. Caelles, and P. Munoz-Canoves The cJun N-terminal kinase (JNK) signaling pathway mediates induction of urokinase-type plasminogen activator (uPA) by the alkylating agent MNNG Blood, August 15, 2000; 96(4): 1415 - 1424. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. Horton, R. Prasad, E. Hou, and S. H. Wilson Protection against Methylation-induced Cytotoxicity by DNA Polymerase beta -Dependent Long Patch Base Excision Repair J. Biol. Chem., January 21, 2000; 275(3): 2211 - 2218. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Atamna, I. Cheung, and B. N. Ames A method for detecting abasic sites in living cells: Age-dependent changes in base excision repair PNAS, January 18, 2000; 97(2): 686 - 691. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. I. Lavrik, R. Prasad, R. W. Sobol, J. K. Horton, E. J. Ackerman, and S. H. Wilson Photoaffinity Labeling of Mouse Fibroblast Enzymes by a Base Excision Repair Intermediate. EVIDENCE FOR THE ROLE OF POLY(ADP-RIBOSE) POLYMERASE-1 IN DNA REPAIR J. Biol. Chem., June 29, 2001; 276(27): 25541 - 25548. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Parra, M. Jardi, M. Koziczak, Y. Nagamine, and P. Munoz-Canoves p53 Phosphorylation at Serine 15 Is Required for Transcriptional Induction of the Plasminogen Activator Inhibitor-1 (PAI-1) Gene by the Alkylating Agent N-Methyl-N'-nitro-N-nitrosoguanidine J. Biol. Chem., September 21, 2001; 276(39): 36303 - 36310. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Garcia-Diaz, K. Bebenek, T. A. Kunkel, and L. Blanco Identification of an Intrinsic 5'-Deoxyribose-5-phosphate Lyase Activity in Human DNA Polymerase lambda . A POSSIBLE ROLE IN BASE EXCISION REPAIR J. Biol. Chem., September 7, 2001; 276(37): 34659 - 34663. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
