DNA double-strand break signaling and human disorders

Mammalian cells and organisms have evolved elegant ways to maintain their genomic integrity and respond to the various DNA lesions that they continuously face. DNA damage can result from exogenous stresses, such as ionizing radiation (IR), ultraviolet (UV) light and chemical compounds, or from endogenous insults such as reactive oxygen species (ROS) and DNA replication errors [1].DNA double-strand breaks (DSBs) are among the most serious and lethal types of DNA damage, as a single DSB is sufficient to kill a cell or disturb its genomic integrity [1]. DSBs are generated in response to exogenous and endogenous DNA insults. For instance, DSBs are induced in response to oncogenic activation [2]. In human precancerous lesions, oncogene activation has been shown to lead to continuous formation of DNA DSBs [3,4]. These DSBs activate the tumor suppressor p53 that mediate apoptosis and/or senescence to restrain the growth of the precancerous cells. In the presence of additional mutations that inactivate p53, precancerous cells become cancerous as they escape p53 mediated apoptosis and/or senescence [5,6]. In addition to the induced DSBs, there are also programmed DSBs that are critical for physiological processes such as meiosis and T and B-cell receptor rearrangements [7,8].DNA damage response (DDR) to various types of DNA insults is a well orchestrated process and is required to maintain genomic integrity (Figure 1) [9-12]. In response to DSBs, a signaling process activates cell cycle checkpoints and pauses cell cycle progression, thus granting time for damaged cells to repair their DNA (Figure 2 and section 2s) [13]. Two major repair pathways for DSBs exist in mammalian cells; the homologous recombination (HR) and the non-homologous end-joining (NHEJ) pathways [14]. The HR pathway is error free but requires an intact homologous template such as a sister chromatid. The NHEJ recombination pathway is the prominent pathway for DSB repair in mammalian cells; however this pathw