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PMID: 15831465 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, P.H.S.

Mismatch repair proteins are activators of toxic responses to chromium-DNA damage.

Molecular and cellular biology ·Vol. 25 ·No. 9 ·2005-05-00 ·Pages 3596-607

Peterson-Roth E, Reynolds M, Quievryn G, Zhitkovich A

Abstract

Chromium(VI) is a toxic and carcinogenic metal that causes the formation of DNA phosphate-based adducts. Cr-DNA adducts are genotoxic in human cells, although they do not block replication in vitro. Here, we report that induction of cytotoxicity in Cr(VI)-treated human colon cells and mouse embryonic fibroblasts requires the presence of all major mismatch repair (MMR) proteins. Cr-DNA adducts lost their ability to block replication of Cr-modified plasmids in human colon cells lacking MLH1 protein. The presence of functional mismatch repair caused induction of p53-independent apoptosis associated with activation of caspases 2 and 7. Processing of Cr-DNA damage by mismatch repair resulted in the extensive formation of gamma-H2AX foci in G(2) phase, indicating generation of double-stranded breaks as secondary toxic lesions. Induction of gamma-H2AX foci was observed at 6 to 12 h postexposure, which was followed by activation of apoptosis in the absence of significant G(2) arrest. Our results demonstrate that mismatch repair system triggers toxic responses to Cr-DNA backbone modifications through stress mechanisms that are significantly different from those for other forms of DNA damage. Selection for Cr(VI) resistant, MMR-deficient cells may explain the very high frequency of lung cancers with microsatellite instability among chromate workers.

MeSH Terms
Adaptor Proteins, Signal Transducing Animals Apoptosis Base Pair Mismatch/genetics,physiology Carrier Proteins Caspase 2 Caspase 7 Caspases/metabolism Cells, Cultured Chromium/toxicity Colon/cytology,drug effects DNA Adducts/metabolism DNA Damage DNA Repair/genetics,physiology DNA Replication/genetics,physiology DNA-Binding Proteins/genetics,physiology Fibroblasts/drug effects G2 Phase/physiology Histones/analysis,metabolism Humans Mice MutL Protein Homolog 1 Neoplasm Proteins/genetics,physiology Nuclear Proteins/genetics,physiology Tumor Suppressor Protein p53/metabolism,physiology
Chemicals
Adaptor Proteins, Signal Transducing Carrier Proteins DNA Adducts DNA-Binding Proteins G-T mismatch-binding protein H2AX protein, human Histones MLH1 protein, human Mlh1 protein, mouse Msh6 protein, mouse Neoplasm Proteins Nuclear Proteins Tumor Suppressor Protein p53 Chromium CASP7 protein, human Casp7 protein, mouse Caspase 2 Caspase 7 Caspases MutL Protein Homolog 1
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Peterson-Roth Elizabeth
Pathology and Laboratory Medicine, Brown University, 70 Ship St., Box G-E507, Providence, RI 02912, USA.
Reynolds Mindy
Quievryn George
Zhitkovich Anatoly
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.25.9.3596-3607.2005
Published
2005-05-00
Pages
3596-607
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1084304
Subset
IM
Grants
NIEHS NIH HHS · R01 ES008786 · United States
NIEHS NIH HHS · 1R01 ES 012915 · United States
NIEHS NIH HHS · 2R01 ES 008786 · United States
NIEHS NIH HHS · 5T32 ES 007272 · United States
NIEHS NIH HHS · R01 ES012915 · United States
NIEHS NIH HHS · T32 ES007272 · United States
External Links
PubMed source DOI: 10.1128/MCB.25.9.3596-3607.2005 PMC Full Text View journal details
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