Genomic instability induced by mutant succinate dehydrogenase subunit D (SDHD) is mediated by O2-&; bull; and H2O2

Kjerstin M Owens; Nukhet Aykin-Burns; Disha Dayal; Mitchell C Coleman; Frederick E Domann; Douglas R Spitz

doi:10.1016/j.freeradbiomed.2011.10.435

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Genomic instability induced by mutant succinate dehydrogenase subunit D (SDHD) is mediated by O2-&; bull; and H2O2

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Genomic instability induced by mutant succinate dehydrogenase subunit D (SDHD) is mediated by O2-&; bull; and H2O2

Kjerstin M Owens, Nukhet Aykin-Burns, Disha Dayal, Mitchell C Coleman, Frederick E Domann and Douglas R Spitz

Free radical biology & medicine, Vol.52(1), pp.160-166

01/01/2012

DOI: 10.1016/j.freeradbiomed.2011.10.435

PMID: 22041456

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https://www.ncbi.nlm.nih.gov/pmc/articles/3249516View

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Abstract

SDHD mutations are associated with human cancers but the mechanisms that may contribute to transformation are unknown. The hypothesis that mutations in SDHD increase levels of superoxide leading to genomic instability was tested using site-directed mutagenesis to generate a truncated SDHD cDNA that was expressed in Chinese hamster fibroblasts. Stable expression of mutant SDHD resulted in 2-fold increases in steady-state levels of superoxide that were accompanied by a significantly increased mutation rate as well as a 70-fold increase in mutation frequency at the hprt locus. Overexpression of MnSOD or treatment with polyethylene glycol conjugated (PEG)-catalase suppressed mutation frequency in SDHD mutant cells by 50% (P < 0.05). Simultaneous treatment with PEG-catalase and PEG-SOD suppressed mutation frequency in SDHD mutant cells by 90% (P < 0.0005). Finally, 95% depletion of glutathione using l-buthionine-[S,R]-sulfoximine (BSO) in SDHD mutant cells caused a 4-fold increase in mutation frequency (P < 0.05). These results demonstrate that mutations in SDHD cause increased steady-state levels of superoxide which significantly contributed to increases in mutation rates and frequency mediated by superoxide and hydrogen peroxide. These results support the hypothesis that mutations in SDHD may contribute to carcinogenesis by increasing genomic instability mediated by increased steady-state levels of reactive oxygen species.

Reactive oxygen species

Succinate dehydrogenase

Transformation

Hydrogen peroxide

Superoxide dismutase

Mutation rates

Superoxide

Carcinogenesis

Genomic instability

Polyethylene glycol

Site-directed mutagenesis

Fibroblasts

Cancer

Glutathione

Details

Title: Subtitle: Genomic instability induced by mutant succinate dehydrogenase subunit D (SDHD) is mediated by O2-&; bull; and H2O2
Creators: Kjerstin M Owens
Nukhet Aykin-Burns
Disha Dayal
Mitchell C Coleman
Frederick E Domann
Douglas R Spitz
Resource Type: Journal article
Publication Details: Free radical biology & medicine, Vol.52(1), pp.160-166
DOI: 10.1016/j.freeradbiomed.2011.10.435
PMID: 22041456
NLM abbreviation: Free Radic Biol Med
ISSN: 0891-5849
eISSN: 1873-4596
Language: English
Date published: 01/01/2012
Academic Unit: Pathology; Orthopedics and Rehabilitation; Surgery; Radiation Oncology
Record Identifier: 9984040016802771

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