X-rays induce distinct patterns of somatic mutation in fetal versus adult hematopoietic cells

Liang, Li; Deng, Li; Mendonca, Marc S.; Chen, Yanping; Zheng, Betty; Stambrook, Peter J.; Shao, Changshun; Tischfield, Jay A.

doi:10.1016/j.dnarep.2007.04.005

Cited by 18 publications

(15 citation statements)

References 21 publications

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“…Nuclear extracts were prepared as previously described [24], and an in-vitro BER assay that measures the short patch BER efficiency of cell extracts was performed [25]. Briefly, a 30-mer oligonucleotide 5′-GAGCCGGCACTGG U GCCCAGCTGATATCGC-3′ containing a uracil at position 14 (underlined) was annealed to the oligonucleotide 5′-GCGATATCAGCTGGGCGCCAGTGCCGGCTC-3′.…”

Section: Methodsmentioning

confidence: 99%

Mismatch and base excision repair proficiency in murine embryonic stem cells

Tichy¹,

Liang²,

Deng³

et al. 2011

DNA Repair

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Accumulation of mutations in embryonic stem (ES) cells would be detrimental to an embryo derived from these cells, and would adversely affect multiple organ systems and tissue types. ES cells have evolved multiple mechanisms to preserve genomic integrity that extend beyond those found in differentiated cell types. The present study queried whether mismatch repair (MMR) and base-excision repair (BER) may play a role in the maintenance of murine ES cell genomes. The MMR proteins Msh2 and Msh6 are highly elevated in mouse ES cells compared with mouse embryo fibroblasts (MEFs), as are Pms2 and Mlh1, albeit to a lesser extent. Cells transfected with an MMR reporter plasmid showed that MMR repair capacity is low in MEFs, but highly active in wildtype ES cells. As expected, an ES cell line defective in MMR was severalfold less effective in repair level than wildtype ES cells. Like proteins that participate in MMR, the level of proteins involved in BER was elevated in ES cells compared with MEFs. When BER activity was examined biochemically using a uracil-containing oligonucleotide template, repair activity was higher in ES cells compared with MEFs. The data are consistent with the suggestion that ES cells have multiple mechanisms, including highly active MMR and BER that preserve genetic integrity and minimize the accumulation of mutations.

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Section: Methodsmentioning

confidence: 99%

Mismatch and base excision repair proficiency in murine embryonic stem cells

Tichy¹,

Liang²,

Deng³

et al. 2011

DNA Repair

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“…If spontaneous mutations leading to LOH at Aprt primarily occur at earlier stages of hematopoietic development, but not in the mature T cells, an assessment of apoptosis in the mature T cells may not necessarily reflect the true nature of the target cells in which mutations arise. Indeed, while x-rays applied to adults preferentially induce deletions and point mutations, they primarily induce mitotic recombination when applied to fetus [24], suggesting that mitotic recombination, which accounts for the majority of the LOH events at Aprt , may primarily occur before birth.…”

Section: Resultsmentioning

confidence: 99%

“…In mice that were exposed to x-rays in their adulthood, there was a clear dose-dependent increase in the Hprt mutant frequency, but the increase in the Aprt mutant frequency was very modest. On the other hand, when x-rays was delivered to fetus in uteri, it had no effect on the Hprt mutant frequency, while Aprt mutant frequency was increased several fold, primarily due to an elevated mitotic recombination [24]. Interestingly, for reason(s) unknown, the mutational response to x-rays at Hprt is not affected by the status of apoptosis.…”

Section: Resultsmentioning

confidence: 99%

Mutagenesis in vivo in T cells of p21-deficient mice

Shao

Liang

Zhao

et al. 2009

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Mice that are deficient in p53 exhibit an early onset of multiple types of tumors, especially thymic lymphoma. However, it remains unclear to what extent each of the p53-regulated pathways exerts its tumor suppressor activity. p21Cip1/Waf1, acting down stream of p53, is a major G1/S checkpoint protein that restricts cell cycle progression into S phase in the presence of DNA damage. While at old ages p21−/− mice have a higher incidence of many types of tumors than p21+/+ mice, they are more resistant to thymic lymphomagenesis. In this study, we characterized mutagenesis in vivo in T cells of p21-deficient mice, using loss of heterozygosity (LOH) at Aprt locus as an indicator. We found that the spontaneous Aprt mutant frequency in T cells of p21−/− mice is lower than that in p21+/+ mice. The mutational spectra, however, are similar, with mitotic recombination being the predominant pathway. In contrast to the remarkable induction of LOH events in T cells of p53−/− mice exposed to x-rays, LOH in T cells of p21−/− mice is not significantly induced by x-rays. Correspondingly, lymphoid cells of p21−/− mice are more sensitive to IR-induced apoptosis than those of p21+/+ mice, in contrast to the radioresistance of p53-deficient lymphocytes. Reduction in mutation load in T cell lineages may contribute to the suppression of thymic lymphomagenesis in p21−/− mice.

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“…This has been supported by previous studies. Differentiated liver cells with high pol β expression exhibited stronger proliferative capacity with accumulation of base loss, misinsertion and/or base substitution than embryonic liver cells with wild-type level of pol β expression (Liang, et al, 2007). It’s also reported that increased pol β activity resulting from enhanced pol β mRNA and protein levels in various types of cancer tissues was remarkably higher than normal tissues (Albertella, et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Involvement of DNA polymerase beta overexpression in the malignant transformation induced by benzo[a]pyrene

Zhao¹,

Wu²,

Lai³

et al. 2013

Toxicology

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Objective To explore the relationship between DNA polymerase β (pol β) overexpression and benzo[a]pyrene (BaP) carcinogenesis. Methods Firstly, mouse embryonic fibroblasts that express wild-type level of DNA polymerase β (pol β cell) and high level of pol β (pol β oe cell) were treated by various concentrations of BaP to determine genetic instability induced by BaP under differential expression levels of pol β. Secondly, malignant transformation of pol β cells by low concentration of BaP (20 μM) was determined by soft agar colony formation assay and transformation focus assay. Thirdly, the mRNA and protein levels of BaP-transformed pol β cells (named pol β-T cells) was measured by reverse transcriptase-polymerase chain reaction (RT-PCR) and western blot, and the genetic instability of these cells were examined by HPRT gene mutation assay and random amplified polymorphic DNA (RAPD) assay. Results Pol β cells were successfully transformed into malignant pol β-T cells by an exposure to low concentration of BaP for 6 months. Pol β-T cells exhibited increased levels of pol β gene expression, HPRT gene mutation frequency and polymorphisms of RAPD products that were comparable to those of pol β oe cells. Conclusion Pol β overexpression and its-associated genetic instability may play a key role in BaP carcinogenesis.

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X-rays induce distinct patterns of somatic mutation in fetal versus adult hematopoietic cells

Cited by 18 publications

References 21 publications

Mismatch and base excision repair proficiency in murine embryonic stem cells

Mismatch and base excision repair proficiency in murine embryonic stem cells

Mutagenesis in vivo in T cells of p21-deficient mice

Involvement of DNA polymerase beta overexpression in the malignant transformation induced by benzo[a]pyrene

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