The Clustered DNA Lesions – Types, Pathways of Repair and Relevance to Human Health

Abstract

The clustered DNA lesions are a characteristic feature of ionizing radiation and are defined as two or more damage sites formed within 20 bps after the passage of a single radiation track. The clustered DNA lesions are divided into two major groups: double-stranded breaks (DSBs) and non-DSB clusters also known as Oxidatively-induced Clustered DNA Lesions (OCDLs), which could involve either two opposing strands or the same strand. As irradiation is gaining greater interest in cancer treatment as well as in imaging techniques, the detailed knowledge of its genotoxicity and the mechanisms of repair of radiation-induced DNA damage remain issues to explore. In this review we look at the ways the cell copes with clustered DNA lesions, especially with 5′,8-cyclo-2′-deoxypurines. As the base excision repair deals with isolated lesions, complex damage is more difficult to repair. Depending on the number of lesions within a cluster, their types and mutual distribution, long-patch BER or NER are activated. During the repair of opposing lesions, DSBs could be generated, which are repaired either by nonhomologous end joining (NHEJ) or homologous recombination (HR). The repair of individual lesions within a cluster progresses gradually. This slower processing of particular damage might lead to severe biological consequences such as misrepair, mutations and chromosomal rearrengement as it enhances the plausibility of a cluster encountering a replication fork prior to its repair. The consequences of clustered DNA lesions on cell survival and their relevance to the efficacy and safety of radiotherapy and radiodiagnosis will also be discussed.