Variations in Prkdc encoding the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) and susceptibility to radiation-induced apoptosis and lymphomagenesis

Mori, Nobuko; Matsumoto, Yoshihisa; Okumoto, Masaaki; Suzuki, Norio; Yamate, Jyoji

doi:10.1038/sj.onc.1204497

Cited by 59 publications

(32 citation statements)

References 40 publications

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“…A deficiency in NHEJ may increase the proportion of double-strand break repaired by alternate pathways such as recombination. BALB/c mice have been found to have two missense mutations in Prkdc, resulting in decreased protein levels, DNA-PK activity and double-strand break joining activity compared with most other mouse strains (36,39,40). This deficiency in DNA-PK function may promote MR, contributing to the higher frequency of LOH via MR for Trp53 observed in the BALB/c strain.…”

Section: Discussionmentioning

confidence: 99%

Loss of Heterozygosity Occurs via Mitotic Recombination in Trp53 +/− Mice and Associates with Mammary Tumor Susceptibility of the BALB/c Strain

et al. 2004

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Section: Discussionmentioning

confidence: 99%

Loss of Heterozygosity Occurs via Mitotic Recombination in Trp53 +/− Mice and Associates with Mammary Tumor Susceptibility of the BALB/c Strain

et al. 2004

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“…Thus, both SCID and A-T mice with distinct deficiencies in DSB repair show kinetics of gH2AX-foci loss, which closely mirror the DSB repair defects of DNA-PKcs -and A-T -mutated-deficient cell systems in vitro (14,22). We also tested BALB/c mice with described radiosensitivity that seems to result from a polymorphism in DNA-PKcs (24,25). Compared with radioresistant C57BL/6 mice, blood lymphocytes derived from radiosensitive BALB/c mice revealed slightly increased foci levels at 5 and 24 hours (P < 0.043) but not at 48 hours postirradiation.…”

Section: Dsb Repair In Blood Lymphocytes (In Vivo)mentioning

confidence: 99%

“…BALB/c mice possess two naturally occurring single nucleotide polymorphisms in the DNA-PKcs gene, which reduce but do not eliminate DNA-PKcs activity (24). Among commonly used inbred mouse strains, BALB/c mice have been consistently found to be unusually radiosensitive (24,25). A-T mice harbor mutations in the A-T -mutated (ATM) protein and are also characterized by increased radiosensitivity and a predisposition to cancer (26 -29).…”

mentioning

confidence: 99%

DNA Double-Strand Break Repair of Blood Lymphocytes and Normal Tissues Analysed in a Preclinical Mouse Model: Implications for Radiosensitivity Testing

Rübe

Grudzenski²,

Kühne³

et al. 2008

Clinical Cancer Research

144

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Purpose: Radiotherapy is an effective cancer treatment, but a few patients suffer severe radiation toxicities in neighboring normal tissues.There is increasing evidence that the variable susceptibility to radiation toxicities is caused by the individual genetic predisposition, by subtle mutations, or polymorphisms in genes involved in cellular responses to ionizing radiation. Doublestrand breaks (DSB) are the most deleterious form of radiation-induced DNA damage, and DSB repair deficiencies lead to pronounced radiosensitivity. Using a preclinical mouse model, the highly sensitive gH2AX-foci approach was tested to verify even subtle, genetically determined DSB repair deficiencies known to be associated with increased normal tissue radiosensitivity. Experimental Design: By enumerating gH2AX-foci in blood lymphocytes and normal tissues (brain, lung, heart, and intestine), the induction and repair of DSBs after irradiation with therapeutic doses (0.1-2 Gy) was investigated in repair-proficient and repair-deficient mouse strains in vivo and blood samples irradiated ex vivo. Results: gH2AX-foci analysis allowed to verify the different DSB repair deficiencies; even slight impairments caused by single polymorphisms were detected similarly in both blood lymphocytes and solid tissues, indicating that DSB repair measured in lymphocytes is valid for different and complex organs. Moreover, gH2AX-foci analysis of blood samples irradiated ex vivo was found to reflect repair kinetics measured in vivo and, thus, give reliable information about the individual DSB repair capacity. Conclusions: gH2AX analysis of blood and tissue samples allows to detect even minor genetically defined DSB repair deficiencies, affecting normal tissue radiosensitivity. Future studies will have to evaluate the clinical potential to identify patients more susceptible to radiation toxicities before radiotherapy.

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“…In addition to the identification of these specific tumour susceptibility genes, genetic analyses of straindependent differences in the short-term apoptotic response of particular cells to particular genotoxins have led to the identification of various loci that control apoptosis in those cells and in some cases, the precise gene has been identified [211][212][213][214][215][216][217]. In an extension of these studies designed to assess the possibility of modifiers of the initial molecular responses and to address tissue-and cell-specific modifiers of radiation responses, we have shown genotype-dependent differences in p53 stabilization and post-translational modification in the spleens of mice after ionizing radiation exposure, confirming the existence of upstream apoptosis modifiers [79,98] (Figure 2).…”

Section: Genetic Factors Influencing Genotoxic Responses and Tumourigmentioning

confidence: 99%

Cell and tissue responses to genotoxic stress

Coates

Lorimore

Wright

2005

The Journal of Pathology

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Cancers arise as a consequence of the accumulation of multiple genetic mutations in a susceptible cell, resulting in perturbation of regulatory networks that control proliferation, survival, and cellular function. Here, the sources of cellular stress that can cause oncogenic mutations and the responses of cells to DNA damage are reviewed. The role of different repair pathways and the potential for cell-and tissue-specific reliance on individual repair mechanisms are discussed. Evidence for cell-and tissue-specific activation of p53-mediated growth arrest and apoptosis after exposure to an individual genotoxin is assessed and some of the potential mediators of these different responses are provided. These cell-and tissuespecific responses to particular forms of DNA damage are likely to be key determinants of tissue-specific tumour susceptibility, and there is good evidence for genetic variations in these responses. The role that genotoxic agents play in altering the microenvironment to produce indirect effects on tumourigenesis through altered production of free radicals and cytokines that are characteristic of inflammatory-type processes is also evaluated. Changes to the microenvironment as direct or indirect effects of genotoxic stress can be involved in both tumour initiation and progression and may even be a prerequisite for tumourigenesis. Therefore, tumour susceptibility after endogenous or exogenous genotoxic stress represents a balance between cell-intrinsic responses of target cells and changes to the microenvironment. A fuller understanding of cell-and tissue-specific responses, alterations to the microenvironment, and genetic modifiers of these responses could lead to novel prevention and therapeutic strategies for common forms of human malignancy.

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Variations in Prkdc encoding the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) and susceptibility to radiation-induced apoptosis and lymphomagenesis

Cited by 59 publications

References 40 publications

Loss of Heterozygosity Occurs via Mitotic Recombination in Trp53 +/− Mice and Associates with Mammary Tumor Susceptibility of the BALB/c Strain

Loss of Heterozygosity Occurs via Mitotic Recombination in Trp53 +/− Mice and Associates with Mammary Tumor Susceptibility of the BALB/c Strain

DNA Double-Strand Break Repair of Blood Lymphocytes and Normal Tissues Analysed in a Preclinical Mouse Model: Implications for Radiosensitivity Testing

Cell and tissue responses to genotoxic stress

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