DNA Double-Strand Break Repair Through Non-Homologous End-Joining: Recruitment and Assembly of the Players

Abstract

DNA, this vitally important genetic macromolecule, is under constant assault via endogenous and exogenous agents which cause damage to DNA and thus to cells leading to genomic instability. The primary endogenous cause of DNA damage is caused during continuous replication of DNA at the S phase of the cell cycle effecting spontaneous mutations. Other endogenous DNA damaging agents are reactive oxygen species (ROS) produced as metabolic byproducts. Additionally, breaks are introduced to DNA in the process of recombination, e.g., V(D)J recombination in immune systems and meiotic recombination in reproductive organs. The exogenous DNA damaging agents are ionizing radiations and chemical compounds, which are intercalated into major or minor grooves of DNA strand or form chemical bond with bases. DNA damages include base elimination, modification, cross-linking and strand break. Strand break includes single-strand break (SSB) and double-strand break (DSB). Among these various types of DNA damages, DSB is considered most fatal. Hence healing DSB is vital to circumvent genomic instability encompassing chromosomal aberrations, translocations and tumorigenesis. Eukaryotes have evolved two major pathways to repair DSBs, i.e., homologous recombination (HR) and non-homologous end-joining (NHEJ). This chapter will review the mechanisms of the latter, especially how the players are recruited to the sites of DSBs and are assembled into multi-protein repair machinery.