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Cited by 89Effects of Radiation ExposureDNA Repair MechanismsCarcinogens and Genotoxicity Assessment

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Targeted and Nontargeted Effects of Ionizing Radiation That Impact Genomic Instability

Maxwell, Christopher A., Fleisch, Markus C., Costes, Sylvain V., Erickson, Anna C., Boissière, Arnaud, Gupta, Rishi, Ravani, Shraddha A., Parvin, Bahram, Barcellos-Hoff, Mary Helen·2008·Cancer Research
DOI 10.1158/0008-5472.can-08-1212

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Abstract

Radiation-induced genomic instability, in which the progeny of irradiated cells display a high frequency of nonclonal genomic damage, occurs at a frequency inconsistent with mutation. We investigated the mechanism of this nontargeted effect in human mammary epithelial cells (HMEC) exposed to low doses of radiation. We identified a centrosome-associated expression signature in irradiated HMEC and show here that centrosome deregulation occurs in the first cell cycle after irradiation, is dose dependent, and that viable daughters of these cells are genomically unstable as evidenced by spontaneous DNA damage, tetraploidy, and aneuploidy. Clonal analysis of genomic instability showed a threshold of >10 cGy. Treatment with transforming growth factor beta1 (TGFbeta), which is implicated in regulation of genomic stability and is activated by radiation, reduced both the centrosome expression signature and centrosome aberrations in irradiated HMEC. Furthermore, TGFbeta inhibition significantly increased centrosome aberration frequency, tetraploidy, and aneuploidy in nonirradiated HMEC. Rather than preventing radiation-induced or spontaneous centrosome aberrations, TGFbeta selectively deleted unstable cells via p53-dependent apoptosis. Together, these studies show that radiation deregulates centrosome stability, which underlies genomic instability in normal human epithelial cells, and that this can be opposed by radiation-induced TGFbeta signaling.

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Crossref · 10.1158/0008-5472.can-08-1212

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  • NTEs have been shown to impact initiation, promotion and progression stages of tumorigenesis at low doses of high LET radiation.

    “NTE have been shown to impact initiation, promotion and progression stages of tumorigenesis at low doses of high LET radiation (Illa-Bochaca et al., 2014;Omene et al., 2020;Maxwell et al., 2008;Kadhim et al., 2013;Lorimore et al., 2003;Barcellos-Hoff and Mao, 2016;Hada et al., 2014;Nagasawa and Little, 1992;Belyakov et al., 2005;Chang et al., 2016).”

    From A proposed change to astronaut exposures limits is a giant leap backwards for radiation protection (2021) · cites this paper as Maxwell et al., 2008

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Metadata

Authors
Maxwell, C. A., Fleisch, M. C., Costes, S. V., Erickson, A. C., Boissière, A., Gupta, R., Ravani, S. A., Parvin, B., & Barcellos-Hoff, M. H.
Affiliations
  • Lawrence Berkeley National Laboratory (US)
  • Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2008-10-15
Volume
68
Issue
20
Pages
8304-8311
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-08-1212
OpenAlex
W2124203681
Cited by
89
References
5
Citations by year
2025: 3 · 2024: 5 · 2023: 8 · 2022: 3 · 2021: 7 · 2020: 9 · 2019: 6 · 2018: 7 · 2017: 3 · 2016: 3 · 2015: 3 · 2014: 6 · 2013: 8 · 2012: 3
FWCI
3.84
Type
journal article
Language
en
Open access
closed
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
Keywords
radiation-induced genomic instability, TGF-β1, human mammary epithelial cells, tetraploidy, aneuploidy, spontaneous DNA damage, p53-dependent apoptosis, low-dose radiation, clonal analysis, cell cycle
MeSH terms
Animals, Breast, Cells, Cultured, Dose-Response Relationship, Radiation, Epithelial Cells, Female, Humans, Mice, Inbred BALB C, Neoplasms, Radiation-Induced, Signal Transduction, Tumor Suppressor Protein p53, Transforming Growth Factor beta, Apoptosis, Centrosome, Genomic Instability, Mice

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