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

Lei Zhao,Chiyuan Ma,Yeqing Sun,Xiaohua Lei,Yuxuan Shang,Dong Mi,Xinye He,Chengyu Bao

doi:10.1155/2020/4834965

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.

Highlights

Ionising radiation (IR), such as X- or γ-rays from medical radiation treatments, high-energy charged (HZE) particles from cosmic radiation, is an unavoidable risk factor to endanger human health [1,2,3,4]
The evolutionarily conserved DNA repair pathways play critical roles in countering and eliciting Ionising radiation- (IR-)induced double-strand breaks (DSBs) to ensure genome integrity and maintain genome stability [8, 9]. If these DNA lesions are not correctly repaired, residual or unrepaired DSBs can lead to the loss of genetic material and cell death, and especially incorrectly repaired DSBs can cause inappropriate endjoining and rearrangement events that may result in gene mutations, chromosome aberrations, cell transformation, carcinogenesis, etc
The results showed that many novel assembly proteins, transcription factors, and molecular chaperones were found to be involved in the IR-induced DNA repair pathways [17]

Summary

Introduction

Ionising radiation (IR), such as X- or γ-rays from medical radiation treatments, high-energy charged (HZE) particles from cosmic radiation, is an unavoidable risk factor to endanger human health [1,2,3,4]. IR can attack DNA and produce a variety of DNA lesions, mainly including DNA double-strand breaks (DSBs), DNA single-strand breaks (SSBs), mismatches, modified bases, and abasic sites, which are associated with various kinds of human diseases [5] Among these DNA lesions, DSBs are considered to be the most deleterious DNA lesions, which are the major threats to genome integrity and stability, and the main factors to determine cellular fate (to survive, to carcinogenesis, or to die) after IR exposures [6, 7]. The evolutionarily conserved DNA repair pathways play critical roles in countering and eliciting IR-induced DSBs to ensure genome integrity and maintain genome stability [8, 9] If these DNA lesions are not correctly repaired, residual or unrepaired DSBs can lead to the loss of genetic material and cell death, and especially incorrectly repaired DSBs can cause inappropriate endjoining and rearrangement events that may result in gene mutations, chromosome aberrations, cell transformation, carcinogenesis, etc. The overarching goal in this review is to summarize and highlight the main factors that probably determine the choices of IR-induced DSB repair pathways from different perspectives, which is of great significance for the mechanistic investigations of DNA repair pathways and consequential choices, the assessments of health risks, and even the developments of radioprotective or radiomitigative drugs after IR exposures

Overview of IR-Induced DNA DSB Repair Pathways

The Determinant of IR-Induced DNA DSB Repair Pathway Choices

DNA-end resection

Conclusion