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Life Sci. 2015 Dec 15;143:80-8. doi: 10.1016/j.lfs.2015.10.028. Epub 2015 Oct 26.

Radiation-induced hyperproliferation of intestinal crypts results in elevated genome instability with inactive p53-related genomic surveillance.

Author information

1
Department of Heavy Ion Radiation Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, PR China; Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000, PR China.
2
Department of Heavy Ion Radiation Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, PR China; The School of Nuclear Science and Technology, Lanzhou University, Lanzhou 730000, PR China; Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000, PR China; University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, 10049, PR China; The National Laboratory for the Heavy Ion Research Facility in Lanzhou, Lanzhou 730000, PR China.
3
Department of Heavy Ion Radiation Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, PR China; Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000, PR China; University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, 10049, PR China.
4
Department of Heavy Ion Radiation Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, PR China; University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, 10049, PR China; The National Laboratory for the Heavy Ion Research Facility in Lanzhou, Lanzhou 730000, PR China.
5
Department of Heavy Ion Radiation Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, PR China; Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000, PR China; The National Laboratory for the Heavy Ion Research Facility in Lanzhou, Lanzhou 730000, PR China. Electronic address: zhangh@impcas.ac.cn.

Abstract

AIMS:

Radiation-induced hyperproliferation of intestinal crypts is well documented, but its potential tumorigenic effects remain elusive. Here we aim to determine the genomic surveillance process during crypt hyperproliferation, and its consequential outcome after ionizing radiation.

MAIN METHODS:

Crypt regeneration in the intestine was induced by a single dose of 12Gy abdominal irradiation. γ-H2AX, 53BP1 and DNA-PKcs were used as DNA repair surrogates to investigate the inherent ability of intestinal crypt cells to recognize and repair double-strand breaks. Ki67 staining and the 5-bromo-2'-deoxyuridine incorporation assay were used to study patterns of cell proliferation in regenerating crypts. Staining for ATM, p53, Chk1 and Chk2 was performed to study checkpoint activation and release. Apoptosis was evaluated through H&E staining and terminal deoxynucleotidyl transferase (dUTP) nick-end labeling.

KEY FINDINGS:

The ATM-p53 pathway was immediately activated after irradiation. A second wave of DSBs in crypt cells was observed in regenerating crypts, accompanied with significantly increased chromosomal bridges. The p53-related genomic surveillance pathway was not active during the regeneration phase despite DSBs and chromosomal bridges in the cells of regenerating crypts. Non-homologous end joining (NHEJ) DSBs repair was involved in the DSBs repair process, as indicated by p-DNA-PKcs staining.

SIGNIFICANCE:

Intestinal crypt cells retained hyperproliferation with inactive p53-related genomic surveillance system. NHEJ was involved in the resultant genomic instability during hyperproliferation.

KEYWORDS:

Hyperproliferation; Intestinal crypt; NHEJ

PMID:
26514305
DOI:
10.1016/j.lfs.2015.10.028
[Indexed for MEDLINE]

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