Prdx1 deficiency in mice promotes tissue specific loss of heterozygosity mediated by deficiency in DNA repair and increased oxidative stress.

Mutation Research
Vamsi RaniJay A Tischfield

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...Continue Reading

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Citations

Mar 18, 2016·Virchows Archiv : an International Journal of Pathology·Pekka PerojaPeeter Karihtala
Oct 11, 2014·Mutation Research. Fundamental and Molecular Mechanisms of Mutagenesis·Bing XuChangshun Shao
Feb 21, 2013·Cell Cycle·Kai Ling ChuSheng-Hao Chao
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Jan 20, 2018·Oxidative Medicine and Cellular Longevity·Nelli RoininenPeeter Karihtala
Apr 6, 2017·Oxidative Medicine and Cellular Longevity·Peeter KarihtalaKirsi-Maria Haapasaari
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Oct 16, 2015·Molecular Genetics and Genomics : MGG·Xinhua HouKui Li
Mar 2, 2021·Frontiers in Cell and Developmental Biology·Hazel J ShieldsJeremy M Van Raamsdonk

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