title: Prdx1 deficiency in mice promotes tissue specific loss of heterozygosity mediated by deficiency in DNA repair and increased oxidative stress.
abstract: The loss of the H(2)O(2) scavenger protein encoded by Prdx1 in mice leads to an elevation of reactive oxygen species (ROS) and tumorigenesis of different tissues. Loss of heterozygosity (LOH) mutations could initiate tumorigenesis through loss of tumor suppressor gene function in heterozygous somatic cells. A connection between the severity of ROS and the frequency of LOH mutations in vivo has not been established. Therefore, in this study, we characterized in vivo LOH in ear fibroblasts and splenic T cells of 3-4 month old Prdx1 deficient mice. We found that the loss of Prdx1 significantly elevates ROS amounts in T cells and fibroblasts. The basal amounts of ROS were higher in fibroblasts than in T cells, probably due to a less robust Prdx1 peroxidase activity in the former. Using Aprt as a LOH reporter, we observed an elevation in LOH mutation frequency in fibroblasts, but not in T cells, of Prdx1(-/-) mice compared to Prdx1(+/+) mice. The majority of the LOH mutations in both cell types were derived from mitotic recombination (MR) events. Interestingly, Mlh1, which is known to suppress MR between divergent sequences, was found to be significantly down-regulated in fibroblasts of Prdx1(-/-) mice. Therefore, the combination of elevated ROS amounts and down-regulation of Mlh1 may have contributed to the elevation of MR in fibroblasts of Prdx1(-/-) mice. We conclude that each tissue may have a distinct mechanism through which Prdx1 deficiency promotes tumorigenesis.
authors.affiliation: Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers University, 145 Bevier Road, Piscataway, NJ 08854, USA.
authors.forename: Vamsi
authors.initials: V
authors.lastname: Rani
authors.forename: Carola A
authors.initials: CA
authors.lastname: Neumann
authors.forename: Changshun
authors.initials: C
authors.lastname: Shao
authors.forename: Jay A
authors.initials: JA
authors.lastname: Tischfield
mesh_terms: D000818:Animals; D004260:DNA Repair; D004423:Ear; D005347:Fibroblasts; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D009154:Mutation; D009928:Organ Specificity; D018384:Oxidative Stress; D054464:Peroxiredoxins / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes
chemical_list: D017382:Reactive Oxygen Species; D054464:Peroxiredoxins; C489899:Prdx1 protein, mouse