Murine Prkdc Polymorphisms Impact DNA-PKcs Function

Fabre, Kristin; Ramaiah, Lila; Dregalla, Ryan C.; Desaintes, Christian; Weil, Michael M.; Bailey, Susan M.; Ullrich, Robert L.

doi:10.1667/rr2431.1

Cited by 11 publications

(7 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It should be mentioned that RLGS studies with mice numbering about 1,000 are not sufficient to indicate that BABL/c mice are more sensitive to radiation for mutation induction in spermatogonia. These results are in line with the results of studies at repair kinetics for radiation-induced DNA double-strand breaks (observed as cH2AX foci): namely, the kinetics were only slightly slower in BALB/c-derived cells compared with B6C3-derived cells (21).…”

Section: Possible Radiation Sensitivity Of the Balb/c Strainsupporting

confidence: 88%

The Genetic Risk in Mice from Radiation: An Estimate of the Mutation Induction Rate per Genome

Asakawa¹,

Kodaira²,

Cullings³

et al. 2013

Radiation Research

View full text Add to dashboard Cite

show abstract

Section: Possible Radiation Sensitivity Of the Balb/c Strainsupporting

confidence: 88%

The Genetic Risk in Mice from Radiation: An Estimate of the Mutation Induction Rate per Genome

Asakawa¹,

Kodaira²,

Cullings³

et al. 2013

Radiation Research

View full text Add to dashboard Cite

show abstract

“…The presented results should be applicable in that analytical context when studying normal tissue effects of radiolabeled agents in tumor-bearing mice. In this context, it should be noted that reduced expression of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and single nucleotide polymorphisms (SNPs) in Prkdc have been reported for several BALB/c strains which affected DNA repair proficiency upon ionizing radiation exposure [ 39 - 43 ]. To the best of our knowledge, the specific strain used in this study has not been categorized regarding DNA repair deficiency, but it is assumed that the genetic background exhibits similarly increased radiation sensitivity.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional response in normal mouse tissues after i.v. 211At administration - response related to absorbed dose, dose rate, and time

et al. 2015

View full text Add to dashboard Cite

BackgroundIn cancer radiotherapy, knowledge of normal tissue responses and toxicity risks is essential in order to deliver the highest possible absorbed dose to the tumor while maintaining normal tissue exposure at non-critical levels. However, few studies have investigated normal tissue responses in vivo after 211At administration. In order to identify molecular biomarkers of ionizing radiation exposure, we investigated genome-wide transcriptional responses to (very) low mean absorbed doses from 211At in normal mouse tissues.MethodsFemale BALB/c nude mice were intravenously injected with 1.7 kBq 211At and killed after 1 h, 6 h, or 7 days or injected with 105 or 7.5 kBq and killed after 1 and 6 h, respectively. Controls were mock-treated. Total RNA was extracted from tissue samples of kidney cortex and medulla, liver, lungs, and spleen and subjected to microarray analysis. Enriched biological processes were categorized after cellular function based on Gene Ontology terms.ResultsResponses were tissue-specific with regard to the number of significantly regulated transcripts and associated cellular function. Dose rate effects on transcript regulation were observed with both direct and inverse trends. In several tissues, Angptl4, Per1 and Per2, and Tsc22d3 showed consistent transcript regulation at all exposure conditions.ConclusionsThis study demonstrated tissue-specific transcriptional responses and distinct dose rate effects after 211At administration. Transcript regulation of individual genes, as well as cellular responses inferred from enriched transcript data, may serve as biomarkers in vivo. These findings expand the knowledge base on normal tissue responses and may help to evaluate and limit side effects of radionuclide therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-014-0078-7) contains supplementary material, which is available to authorized users.

show abstract

“…The numerous γH2AX foci of the Scid mice displayed in Fig. 5C may explain their susceptibility to mammary adenocarcinoma (49).…”

Section: Brca1 Promotes the Mre11-dependent Removal Of 5′ Adducts Frommentioning

confidence: 97%

BRCA1 ensures genome integrity by eliminating estrogen-induced pathological topoisomerase II–DNA complexes

Sasanuma

Tsuda

Morimoto

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Women having BRCA1 germ-line mutations develop cancer in breast and ovary, estrogen-regulated tissues, with high penetrance. Binding of estrogens to the estrogen receptor (ER) transiently induces DNA double-strand breaks (DSBs) by topoisomerase II (TOP2) and controls gene transcription. TOP2 resolves catenated DNA by transiently generating DSBs, TOP2-cleavage complexes (TOP2ccs), where TOP2 covalently binds to 5′ ends of DSBs. TOP2 frequently fails to complete its catalysis, leading to formation of pathological TOP2ccs. We have previously shown that the endonucleolytic activity of MRE11 plays a key role in removing 5′ TOP2 adducts in G1phase. We show here that BRCA1 promotes MRE11-mediated removal of TOP2 adducts in G1phase. We disrupted theBRCA1gene in53BP1-deficient ER-positive breast cancer and B cells. The loss of BRCA1 caused marked increases of pathological TOP2ccs in G1phase following exposure to etoposide, which generates pathological TOP2ccs. We conclude that BRCA1 promotes the removal of TOP2 adducts from DSB ends for subsequent nonhomologous end joining.BRCA1-deficient cells showed a decrease in etoposide-induced MRE11 foci in G1phase, suggesting that BRCA1 repairs pathological TOP2ccs by promoting the recruitment of MRE11 to TOP2cc sites. BRCA1 depletion also leads to the increase of unrepaired DSBs upon estrogen treatment both in vitro in G1-arrested breast cancer cells and in vivo in epithelial cells of mouse mammary glands. BRCA1 thus plays a critical role in removing pathological TOP2ccs induced by estrogens as well as etoposide. We propose that BRCA1 suppresses tumorigenesis by removing estrogen-induced pathological TOP2ccs throughout the cell cycle.

show abstract

Murine Prkdc Polymorphisms Impact DNA-PKcs Function

Cited by 11 publications

References 28 publications

The Genetic Risk in Mice from Radiation: An Estimate of the Mutation Induction Rate per Genome

The Genetic Risk in Mice from Radiation: An Estimate of the Mutation Induction Rate per Genome

Transcriptional response in normal mouse tissues after i.v. 211At administration - response related to absorbed dose, dose rate, and time

BRCA1 ensures genome integrity by eliminating estrogen-induced pathological topoisomerase II–DNA complexes

Contact Info

Product

Resources

About