title: Induction of DNA-protein cross-links by ionizing radiation and their elimination from the genome.
abstract: 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.
authors.affiliation: Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi-Hiroshima 739-8526, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Nakano
authors.affiliation: Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi-Hiroshima 739-8526, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Mitsusada
authors.affiliation: Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi-Hiroshima 739-8526, Japan; Department of Pathology, Medical Research Division, National Research Centre, El-Bohouth St., Dokki, Giza 12311, Egypt.
authors.forename: Amir M H
authors.initials: AM
authors.lastname: Salem
authors.affiliation: Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi-Hiroshima 739-8526, Japan; Department of Zoology, Biological Science Building, Faculty of Science, Minia University, Minia 61519, Egypt.
authors.forename: Mahmoud I
authors.initials: MI
authors.lastname: Shoulkamy
authors.affiliation: Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi-Hiroshima 739-8526, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Sugimoto
authors.affiliation: Research Center for Charged Particle Therapy, National Institute of Radiological Sciences (NIRS), Chiba 263-8555, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Hirayama
authors.affiliation: Research Center for Charged Particle Therapy, National Institute of Radiological Sciences (NIRS), Chiba 263-8555, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Uzawa
authors.affiliation: Development and Support Center, National Institute of Radiological Sciences (NIRS), Chiba 263-8555, Japan.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Furusawa
authors.affiliation: Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi-Hiroshima 739-8526, Japan. Electronic address: ideh@hiroshima-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ide
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects*; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016678:Genome; D063193:Heavy Ion Radiotherapy; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D014965:X-Rays
chemical_list: D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins
keywords: C-ion beam; DNA double-strand break; DNA–protein cross-link; Hypoxic tumor; X-ray