HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 29, 30419-30424, July 16, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/29/30419    most recent M402486200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Reynolds, M. Articles by Zhitkovich, A. Search for Related Content PubMed PubMed Citation Articles by Reynolds, M. Articles by Zhitkovich, A. Social Bookmarking                      What's this?

Human Nucleotide Excision Repair Efficiently Removes Chromium-DNA Phosphate Adducts and Protects Cells against Chromate Toxicity^*

Mindy Reynolds, Elizabeth Peterson, George Quievryn, and Anatoly Zhitkovich

From the Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island 02912

Intracellular reduction of carcinogenic Cr(VI) leads to the extensive formation of Cr(III)-DNA phosphate adducts. Repair mechanisms for chromium and other DNA phosphate-based adducts are currently unknown in human cells. We found that nucleotide excision repair (NER)-proficient human cells rapidly removed chromium-DNA adducts, with an average t of 7.1 h, whereas NER-deficient XP-A, XP-C, and XP-F cells were severely compromised in their ability to repair chromium-DNA lesions. Activation of NER in Cr(VI)-treated human fibroblasts or lung epithelial H460 cells was manifested by XPC-dependent binding of the XPA protein to the nuclear matrix, which was also observed in UV light-treated (but not oxidant-stressed) cells. Intracellular replication of chromium-modified plasmids demonstrated increased mutagenicity of binary Cr(III)-DNA and ternary cysteine-Cr(III)-DNA adducts in cells with inactive NER. NER deficiency created by the loss of XPA in fibroblasts or by knockdown of this protein by stable expression of small interfering RNA in H460 cells increased apoptosis and clonogenic death by Cr(VI), providing genetic evidence for the role of monofunctional chromium-DNA adducts in the toxic effects of this metal. The rate of NER of chromium-DNA adducts under saturating conditions was calculated to be 50,000 lesions/min/cell. Because chromium-DNA adducts cause only small changes in the DNA helix, rapid repair of these modifications in human cells indicates that the presence of major structural distortions in DNA is not required for the efficient detection of the damaged sites by NER proteins in vivo.

Received for publication, March 4, 2004 , and in revised form, April 12, 2004.

^* This work was supported by National Institutes of Health Grants 2R01 ES008786, 5T32 ES007272, and 1P20 RR015578. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Pathology and Laboratory Medicine, Brown University, 69 Brown St., P. O. Box G-B511, Providence, RI 02912. Tel.: 401-863-2912; Fax; 401-863-9008; E-mail: Anatoly_Zhitkovich{at}brown.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. A. Nemec and A. Barchowsky Signal Transducer and Activator of Transcription 1 (STAT1) is Essential for Chromium Silencing of Gene Induction in Human Airway Epithelial Cells Toxicol. Sci., July 1, 2009; 110(1): 212 - 223. [Abstract] [Full Text] [PDF]

				M. F. Reynolds, E. C. Peterson-Roth, I. A. Bespalov, T. Johnston, V. M. Gurel, H. L. Menard, and A. Zhitkovich Rapid DNA Double-Strand Breaks Resulting from Processing of Cr-DNA Cross-Links by Both MutS Dimers Cancer Res., February 1, 2009; 69(3): 1071 - 1079. [Abstract] [Full Text] [PDF]

				R. Branco, A. P. Chung, T. Johnston, V. Gurel, P. Morais, and A. Zhitkovich The Chromate-Inducible chrBACF Operon from the Transposable Element TnOtChr Confers Resistance to Chromium(VI) and Superoxide J. Bacteriol., November 1, 2008; 190(21): 6996 - 7003. [Abstract] [Full Text] [PDF]

				B. Brooks, T. J. O'Brien, S. Ceryak, J. P. Wise Sr, S. S. Wise, J. P. Wise Jr, E. DeFabo, and S. R. Patierno Excision repair is required for genotoxin-induced mutagenesis in mammalian cells Carcinogenesis, May 1, 2008; 29(5): 1064 - 1069. [Abstract] [Full Text] [PDF]

				M. Schnekenburger, G. Talaska, and A. Puga Chromium Cross-Links Histone Deacetylase 1-DNA Methyltransferase 1 Complexes to Chromatin, Inhibiting Histone-Remodeling Marks Critical for Transcriptional Activation Mol. Cell. Biol., October 15, 2007; 27(20): 7089 - 7101. [Abstract] [Full Text] [PDF]

				M. Reynolds and A. Zhitkovich Cellular vitamin C increases chromate toxicity via a death program requiring mismatch repair but not p53 Carcinogenesis, July 1, 2007; 28(7): 1613 - 1620. [Abstract] [Full Text] [PDF]

				H. Ziaee, J. Daniel, A. K. Datta, S. Blunt, and D. J. W. McMinn Transplacental transfer of cobalt and chromium in patients with metal-on-metal hip arthroplasty: A CONTROLLED STUDY J Bone Joint Surg Br, March 1, 2007; 89-B(3): 301 - 305. [Abstract] [Full Text] [PDF]

				J. Daniel, H. Ziaee, C. Pradhan, P. B. Pynsent, and D. J. W. McMinn Blood and urine metal ion levels in young and active patients after Birmingham hip resurfacing arthroplasty: FOUR-YEAR RESULTS OF A PROSPECTIVE LONGITUDINAL STUDY J Bone Joint Surg Br, February 1, 2007; 89-B(2): 169 - 173. [Abstract] [Full Text] [PDF]

				M. Reynolds, L. Stoddard, I. Bespalov, and A. Zhitkovich Ascorbate acts as a highly potent inducer of chromate mutagenesis and clastogenesis: linkage to DNA breaks in G2 phase by mismatch repair Nucleic Acids Res., January 28, 2007; 35(2): 465 - 476. [Abstract] [Full Text] [PDF]

				G. Quievryn, J. Messer, and A. Zhitkovich Lower mutagenicity but higher stability of Cr-DNA adducts formed during gradual chromate activation with ascorbate Carcinogenesis, November 1, 2006; 27(11): 2316 - 2321. [Abstract] [Full Text] [PDF]

				Q.-E. Wang, Q. Zhu, G. Wani, M. A. El-Mahdy, J. Li, and A. A. Wani DNA repair factor XPC is modified by SUMO-1 and ubiquitin following UV irradiation Nucleic Acids Res., July 19, 2005; 33(13): 4023 - 4034. [Abstract] [Full Text] [PDF]

				E. R. Sumner, A. Shanmuganathan, T. C. Sideri, S. A. Willetts, J. E. Houghton, and S. V. Avery Oxidative protein damage causes chromium toxicity in yeast Microbiology, June 1, 2005; 151(6): 1939 - 1948. [Abstract] [Full Text] [PDF]

				E. Peterson-Roth, M. Reynolds, G. Quievryn, and A. Zhitkovich Mismatch Repair Proteins Are Activators of Toxic Responses to Chromium-DNA Damage Mol. Cell. Biol., May 1, 2005; 25(9): 3596 - 3607. [Abstract] [Full Text] [PDF]