Induction of DNA-protein cross-links by ionizing radiation and their elimination from the genome

Ionizing radiation produces various types of DNA lesions, such as base damage, single-strand breaks, double-strand breaks (DSBs), and DNA-protein cross-links (DPCs). Of these, DSBs are the most critical lesions underlying the lethal effects of ionizing radiation. With DPCs, proteins covalently trapp...

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Bibliographic Details
Published in:	Mutation research Vol. 771; p. 45
Main Authors:	Nakano, Toshiaki, Mitsusada, Yusuke, Salem, Amir M H, Shoulkamy, Mahmoud I, Sugimoto, Tatsuya, Hirayama, Ryoichi, Uzawa, Akiko, Furusawa, Yoshiya, Ide, Hiroshi
Format:	Journal Article
Language:	English
Published:	Netherlands 01-01-2015
Subjects:	Animals Carcinoma, Squamous Cell - genetics Carcinoma, Squamous Cell - metabolism Carcinoma, Squamous Cell - pathology Carcinoma, Squamous Cell - radiotherapy Cell Hypoxia Cell Line, Tumor DNA Breaks, Double-Stranded - radiation effects DNA, Neoplasm - genetics DNA, Neoplasm - metabolism DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Genome Heavy Ion Radiotherapy Male Mice Neoplasm Proteins - genetics Neoplasm Proteins - metabolism X-Rays DNA–protein cross-link X-ray C-ion beam Hypoxic tumor DNA double-strand break
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Summary:	Ionizing radiation produces various types of DNA lesions, such as base damage, single-strand breaks, double-strand breaks (DSBs), and DNA-protein cross-links (DPCs). Of these, DSBs are the most critical lesions underlying the lethal effects of ionizing radiation. With DPCs, proteins covalently trapped in DNA constitute strong roadblocks to replication and transcription machineries, and hence can be lethal to cells. The formation of DPCs by ionizing radiation is promoted in the absence of oxygen, whereas that of DSBs is retarded. Accordingly, the contribution of DPCs to the lethal events in irradiated cells may not be negligible for hypoxic cells, such as those present in tumors. However, the role of DPCs in the lethal effects of ionizing radiation remains largely equivocal. In the present study, normoxic and hypoxic mouse tumors were irradiated with X-rays [low linear energy transfer (LET) radiation] and carbon (C)-ion beams (high LET radiation), and the resulting induction of DPCs and DSBs and their removal from the genome were analyzed. X-rays and C-ion beams produced more DPCs in hypoxic tumors than in normoxic tumors. Interestingly, the yield of DPCs was slightly but statistically significantly greater (1.3- to 1.5-fold) for C-ion beams than for X-rays. Both X-rays and C-ion beams generated two types of DPC that differed according to their rate of removal from the genome. This was also the case for DSBs. The half-lives of the rapidly removed components of DPCs and DSBs were similar (<1 h), but those of the slowly removed components of DPCs and DSBs were markedly different (3.9-5 h for DSBs versus 63-70 h for DPCs). The long half-life and abundance of the slowly removed DPCs render them persistent in DNA, which may impede DNA transactions and confer deleterious effects on cells in conjunction with DSBs.
ISSN:	1873-135X
DOI:	10.1016/j.mrfmmm.2014.12.003