The Determinant of DNA Repair Pathway Choices in Ionising Radiation-Induced DNA Double-Strand Breaks

Abstract

Ionising radiation- (IR-) induced DNA double-strand breaks (DSBs) are considered to be the deleterious DNA lesions that pose a serious threat to genomic stability. The major DNA repair pathways, including classical nonhomologous end joining, homologous recombination, single-strand annealing, and alternative end joining, play critical roles in countering and eliciting IR-induced DSBs to ensure genome integrity. If the IR-induced DNA DSBs are not repaired correctly, the residual or incorrectly repaired DSBs can result in genomic instability that is associated with certain human diseases. Although many efforts have been made in investigating the major mechanisms of IR-induced DNA DSB repair, it is still unclear what determines the choices of IR-induced DNA DSB repair pathways. In this review, we discuss how the mechanisms of IR-induced DSB repair pathway choices can operate in irradiated cells. We first briefly describe the main mechanisms of the major DNA DSB repair pathways and the related key repair proteins. Based on our understanding of the characteristics of IR-induced DNA DSBs and the regulatory mechanisms of DSB repair pathways in irradiated cells and recent advances in this field, We then highlight the main factors and associated challenges to determine the IR-induced DSB repair pathway choices. We conclude that the type and distribution of IR-induced DSBs, chromatin state, DNA-end structure, and DNA-end resection are the main determinants of the choice of the IR-induced DNA DSB repair pathway.

Figure 1

(a) Major repair pathways for DNA double-strand breaks (DSBs) generated by ionising radiation (IR). When IR-induced DNA DSBs have blunt double-strand DNA ends or contain short single-strand DNA ends, the classical nonhomologous end joining (c-NHEJ) is initiated by the binding of the Ku70/80 heterodimer followed by the recruitment of DNA-PKcs and polymerase. When DNA resection occurs, the pathways of homologous recombination (HR), alternative end joining (alt-EJ), and single-strand annealing (SSA) can be activated to repair the IR-induced DNA DSBs by the recruitments of different proteins. (b–e) The major repair pathways ((b) c-NHEJ, (c) HR, (d) SSA, and (e) alt-EJ) for processing IR-induced DNA DSBs have a distinct cell-cycle dependence.

Figure 2

The direct and indirect effects of ionising radiation (IR) in cells. The schematic shows IR can lead to the DNA double-strand breaks (DSBs) directly by the induction of radiation energy deposition, or indirectly by the generation of reactive oxygen and nitrogen species (ROS and RNS). The direct effects are mainly determined by the radiation quality, i.e., low and high linear energy transfer (LET) can generate distinctive patterns of ionisation events on the structures of DNA molecules. When doses are the same, low-LET (a) and high-LET (b) radiation can generate different types and distributions of DNA DSBs. The IR-induced ROS and RNS are not only from the interaction of IR with water and molecules but also as a result of leakage of mitochondrial dysfunctions.

Figure 3

The choices of ionising radiation- (IR-) induced DNA repair pathways. The schematic shows that there are four key factors, including the chromatin state, the type and distribution of IR-induced DNA double-strand breaks (DSBs), the DNA-end structure, and the DNA-end resection, which can determine the repair pathway choices. Many critical proteins that are directly or indirectly involved in the above processes also play a critical role in determining the pathway choices. The more detailed discussions can be found in the main text.