Sage Evelyne, Shikazono Naoya
Institut Curie, PSL Research University, CNRS, UMR3347, F-91405 Orsay, France.
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.
Free Radic Biol Med. 2017 Jun;107:125-135. doi: 10.1016/j.freeradbiomed.2016.12.008. Epub 2016 Dec 8.
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.
簇状DNA损伤，也称为多重损伤位点，是电离辐射的标志。它被定义为两个或更多损伤的组合，包括链断裂、氧化产生的碱基损伤、在一个或两个DNA螺旋圈内的无碱基位点，由单个辐射径迹的通过产生。双链断裂簇状损伤将双链断裂与几个相邻的碱基损伤和无碱基位点联系在一起，并被归类为复杂双链断裂。非双链断裂簇状损伤包括单链断裂、碱基损伤和无碱基位点。在低传能线密度（LET）的辐射下，如X射线或γ射线，簇状DNA损伤的数量比双链断裂多3 - 4倍。它们的比例和复杂性随着LET的增加而增加；它们可能占DNA损伤的很大一部分。使用复杂性不断增加的工程化簇状DNA损伤进行的体外研究极大地增进了我们对非双链断裂簇状损伤处理方式的理解。碱基切除修复受到损害，在一个簇内损伤处理过程中观察到的层级关系导致形成单链断裂或双链断裂作为修复中间体，并增加了损伤的持续时间。因此，突变的几率急剧增加。复杂双链断裂，无论是直接由辐射形成还是由非双链断裂簇状损伤的处理形成，都通过缓慢的动力学进行修复或未被修复，导致细胞死亡或通过有丝分裂。在存活的细胞中，观察到大量的缺失、易位和染色体畸变。这篇综述详细介绍了关于非双链断裂簇状损伤和复杂双链断裂处理的最新数据，并倾向于证明这些特定DNA损伤在诱导基因组不稳定性方面的高度重要性。
