title: Radiation-induced clustered DNA lesions: Repair and mutagenesis.
abstract: Clustered DNA lesions, also called Multiply Damaged Sites, is the hallmark of ionizing radiation. It is defined as the combination of two or more lesions, comprising strand breaks, oxidatively generated base damage, abasic sites within one or two DNA helix turns, created by the passage of a single radiation track. DSB clustered lesions associate DSB and several base damage and abasic sites in close vicinity, and are assimilated to complex DSB. Non-DSB clustered lesions comprise single strand break, base damage and abasic sites. At radiation with low Linear Energy Transfer (LET), such as X-rays or γ-rays clustered DNA lesions are 3-4 times more abundant than DSB. Their proportion and their complexity increase with increasing LET; they may represent a large part of the damage to DNA. Studies in vitro using engineered clustered DNA lesions of increasing complexity have greatly enhanced our understanding on how non-DSB clustered lesions are processed. Base excision repair is compromised, the observed hierarchy in the processing of the lesions within a cluster leads to the formation of SSB or DSB as repair intermediates and increases the lifetime of the lesions. As a consequence, the chances of mutation drastically increase. Complex DSB, either formed directly by irradiation or by the processing of non-DSB clustered lesions, are repaired by slow kinetics or left unrepaired and cause cell death or pass mitosis. In surviving cells, large deletions, translocations, and chromosomal aberrations are observed. This review details the most recent data on the processing of non-DSB clustered lesions and complex DSB and tends to demonstrate the high significance of these specific DNA damage in terms of genomic instability induction.
authors.affiliation: Institut Curie, PSL Research University, CNRS, UMR3347, F-91405 Orsay, France. Electronic address: evelyne.sage@curie.fr.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Sage
authors.affiliation: Quantum Beam Science Research Directorate, National Institutes of Quantum and Radiological Science and Technology, Kansai Photon Science Institute, 8-1-7 Umemidai, Kizugawa-Shi, Kyoto 619-0215, Japan. Electronic address: shikazono.naoya@qst.go.jp.
authors.forename: Naoya
authors.initials: N
authors.lastname: Shikazono
mesh_terms: D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair; D005818:Genetic Engineering; D042822:Genomic Instability; D006801:Humans; D018499:Linear Energy Transfer; D005810:Multigene Family / Q000235:genetics*; D016296:Mutagenesis; D011839:Radiation, Ionizing
keywords: Base excision repair; Clustered DNA lesions; Complex DSB; DNA repair; Ionizing radiation; Multiply damaged sites; Non-DSB clustered lesions; Oxidatively generated DNA damage