Naumenko N V, Petruseva I O, Lavrik O I
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090 Russia.
Acta Naturae. 2022 Oct-Dec;14(4):38-49. doi: 10.32607/actanaturae.11741.
The nucleotide excision repair (NER) system removes a wide range of bulky DNA lesions that cause significant distortions of the regular double helix structure. These lesions, mainly bulky covalent DNA adducts, are induced by ultraviolet and ionizing radiation or the interaction between exogenous/endogenous chemically active substances and nitrogenous DNA bases. As the number of DNA lesions increases, e.g., due to intensive chemotherapy and combination therapy of various diseases or DNA repair impairment, clustered lesions containing bulky adducts may occur. Clustered lesions are two or more lesions located within one or two turns of the DNA helix. Despite the fact that repair of single DNA lesions by the NER system in eukaryotic cells has been studied quite thoroughly, the repair mechanism of these lesions in clusters remains obscure. Identification of the structural features of the DNA regions containing irreparable clustered lesions is of considerable interest, in particular due to a relationship between the efficiency of some antitumor drugs and the activity of cellular repair systems. In this review, we analyzed data on the induction of clustered lesions containing bulky adducts, the potential biological significance of these lesions, and methods for quantification of DNA lesions and considered the causes for the inhibition of NER-catalyzed excision of clustered bulky lesions.
核苷酸切除修复（NER）系统可去除多种导致规则双螺旋结构严重扭曲的大体积DNA损伤。这些损伤主要是大体积共价DNA加合物，由紫外线和电离辐射或外源性/内源性化学活性物质与含氮DNA碱基之间的相互作用诱导产生。随着DNA损伤数量的增加，例如由于各种疾病的强化化疗和联合治疗或DNA修复受损，可能会出现包含大体积加合物的簇状损伤。簇状损伤是指位于DNA螺旋一到两圈内的两个或更多损伤。尽管真核细胞中NER系统对单个DNA损伤的修复已得到相当深入的研究，但这些簇状损伤的修复机制仍不清楚。鉴定包含无法修复的簇状损伤的DNA区域的结构特征具有相当大的意义，特别是因为一些抗肿瘤药物的疗效与细胞修复系统的活性之间存在关联。在本综述中，我们分析了有关包含大体积加合物的簇状损伤的诱导、这些损伤的潜在生物学意义以及DNA损伤定量方法的数据，并探讨了抑制NER催化切除簇状大体积损伤的原因。
