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PMID: 16283517 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Nucleotide excision repair functions in the removal of chromium-induced DNA damage in mammalian cells.

Molecular and cellular biochemistry ·Vol. 279 ·No. 1-2 ·2005-11-00 ·Pages 85-95

O'Brien TJ, Brooks BR, Patierno SR

Abstract

Some hexavalent chromium (Cr(VI))-containing compounds are human lung carcinogens. While ample information is available on the genetic lesions produced by Cr, surprisingly little is known regarding the cellular mechanisms involved in the removal of Cr-DNA adducts. Nucleotide excision repair (NER) is a highly versatile pathway that is responsive to a variety of DNA helix-distorting lesions. Binary Cr-DNA monoadducts do not produce a significant degree of helical distortion. However, these lesions are unstable due to the propensity of Cr(III) to form DNA adducts (DNA interstrand crosslinks, DNA-protein/amino acid ternary adducts) which may serve as substrates for NER. Therefore, the focus of this study was to determine the role of NER in the processing of Cr-DNA damage using normal (CHO-AA8) and NER-deficient [UV-5 (XP-D); UV-41 (ERCC4/XP-F)] hamster cells. We found that both UV-5 and UV-41 cells exhibited an increased sensitivity towards Cr(VI)-induced clonogenic lethality relative to AA8 cells and were completely deficient in the removal of Cr-DNA adducts. In contrast, repair-complemented UV-5 (expressing hamster XPD) and UV-41 (expressing human ERCC4) cells exhibited similar clonogenic survival and removed Cr-DNA adducts to a similar extent as AA8 cells. In order to extend these findings to the molecular level, we examined the ability of Cr(III)-damaged DNA to induce DNA repair synthesis in cell extracts. Repair synthesis was observed in reactions using extracts derived from AA8, or repair-complemented, but not NER-deficient cells. Cr(III)-induced repair resynthesis was sensitive to inhibition by the DNA polymerase delta/epsilon inhibitor, aphidicolin, but not 2',3'-dideoxythymidine triphosphate (ddTTP), a polymerase beta inhibitor. These results collectively suggest that NER functions in the protection of cells from Cr(VI) lethality and is essential for the removal of Cr(III)-DNA adducts. Consequently, NER may represent an important mechanism for preventing Cr(VI)-induced mutagenesis and neoplastic transformation.

MeSH Terms
Animals Aphidicolin/pharmacology CHO Cells Cell Survival/drug effects Chlorides/toxicity Chromium/toxicity Chromium Compounds/toxicity Cricetinae Cricetulus DNA Adducts/metabolism DNA Damage DNA Repair/drug effects DNA-Binding Proteins/deficiency,genetics,metabolism Enzyme Inhibitors/pharmacology HeLa Cells Humans Mutagens/toxicity Nucleic Acid Synthesis Inhibitors Plasmids Subcellular Fractions/metabolism Transfection Xeroderma Pigmentosum Group D Protein/deficiency,genetics,metabolism
Chemicals
Chlorides Chromium Compounds DNA Adducts DNA-Binding Proteins Enzyme Inhibitors Mutagens Nucleic Acid Synthesis Inhibitors xeroderma pigmentosum group F protein Chromium chromium hexavalent ion Aphidicolin Xeroderma Pigmentosum Group D Protein chromic chloride
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
O'Brien Travis J
Department of Pharmacology and Physiology, The George Washington University Medical Center, Washington, DC 20037, USA. [email protected]
Brooks Bradford R
Patierno Steven R
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Article Info
Journal
Molecular and cellular biochemistry
Abbr.
Mol Cell Biochem
ISSN
0300-8177
DOI
10.1007/s11010-005-8225-0
Email
[email protected]
Published
2005-11-00
Pages
85-95
Language
English
Region
Netherlands
NLM ID
0364456
Subset
IM
Grants
NIEHS NIH HHS · ES05304 · United States
External Links
PubMed source DOI: 10.1007/s11010-005-8225-0 View journal details
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