Repair of radiation damage to DNA

Abstract

DNA double-strand breaks constitute the most dangerous type of DNA damage induced by ionising radiation (IR). Accordingly, the resistance of cells to IR is modulated by three intimately related cellular processes: DNA repair, recombination, and replication. Significant discoveries in this field of research have been made over the last few years. A picture seems to be emerging in which perturbations of recombination in cancer cells are a more widespread cause of genomic instability than previously appreciated. Conversely, such cells may also be more sensitive to certain chemotherapeutic drugs and to IR. Thus, the alterations in recombination that promote carcinogenesis by causing genomic instability may also be the weakness of the tumours that arise in this setting, a concept which could hold great promise for the advancement of cancer treatment in the not too distant future. British Journal of Cancer (2004) (Steel, 1996). It is established that the creation of a DNA double-strand break (DSB) represents the principal lesion that, if not adequately repaired, can lead to cell death via the generation of lethal chromosomal aberrations or the direct induction of apoptosis. Alternatively, an inaccurately repaired or unrepaired DSB may result in mutations or genomic rearrangements in a surviving cell, which in turn can lead to genomic instability and subsequently result in malignant cell transformation. Complex damage response pathways have evolved, and are evolutionary conserved, to protect the cell from the potentially deleterious effects of a DSB. Two principal recombinational repair pathways have been recognised, homologous recombination (HR) and nonhomologous end-joining (NHEJ), that employ entirely separate protein complexes. Briefly, DSB repair by HR requires an undamaged template molecule that contains a homologous DNA sequence, typically on the sister chromatid in the S and G2 phases of the cell cycle. In contrast, nonhomologous re-joining of two double-stranded DNA ends, which may occur in all cell-cycle phases, does not require an undamaged partner and does not rely on extensive homologies between the recombining ends. The study of these pathways has proved to be a rapidly evolving field of research over the past few years. Considerable interest has been generated by the realisation that defective HR and, in some cases, NHEJ can be causally linked to impaired DNA replication, genomic instability, human chromosomal instability syndromes, cancer development, or cellular hypersensitivity to DNA-damaging agents.Here, we discuss some of the recent advancements in basic research on DNA repair, recombination, and replication, which could hold great promise for the advancement of cancer treatment in the not too distant future. To this end, the prevailing theme is that the genetic alterations in recombination that lead to genomic instability and malignant transformation may also determine how tumour cells respond to IR and certain chemotherapeutic drugs (Venkitaraman, 2003). We are only able to consider a small numbe...

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“…NA double-strand breaks (DSBs), which can arise from endogenous or exogenous sources, particularly ionizing radiation (IR), are considered among the most lethal and genome-destabilizing types of DNA damage (Pierce et al 2001;Willers et al 2004). Efficient and accurate repair of DSBs is essential to preserve genome integrity.…”