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Introduction
DNA double-strand breaks (DSBs) arising from a number of endogenous and exogenous sources, such as oxidative stress and ionizing radiation (IR), can induce the DNA damage response (DDR) (1). As an important mechanism of maintenance of genomic integrity, the DDR cascade senses genome damage and activates several downstream pathways including cell cycle checkpoints and DNA repair, to protect cancer cells from DNA damage. Ataxia telangiectasia-mutated (ATM) and ATM-related (ATR) kinases are phosphoinositol 3-kinase-like kinases (PIKKs) that regulate the DNA damage signaling response (2,3). Once activated, ATM and ATR in turn phosphorylate the histone variant H2AX and downstream effectors, including the Chk1 and Chk2 cell cycle kinases, resulting in cell cycle checkpoint activation and cell cycle arrest. The checkpoint activation frequently leads to modifications of DNA repair factors and results in a more efficient removal of the lesions and increased resistance to further damage. The cell cycle arrest of cancer cells induced by IR damage is the main reason of radioresistance (4).
An emerging classification of proteins termed mediators participates in the transduction of the checkpoint response (5). These proteins are thought to be involved in the recognition of DNA damage and the recruitment of additional proteins that facilitate downstream signaling and repair. Important mediators are mediators of DNA damage checkpoint l (MDC1) and p53 binding protein l (53BP1), which participated in the signaling pathway initiated by ATM (6,7). MDC1, containing functional domains such as forkhead-associated domain (FHA) and BRCA1 carboxy-terminal (BRCT) domains, can recognize the phosphorylated H2AX proximal to the lesion via its tandem BRCT domain and help to counter H2AX dephosphorylation. As a mediator protein, MDC1 is localized to the damage site independently of ATM but is recruited to the damage site through interaction with ATM-phosphorylated histone H2AX and distributed along the damaged region (8,9). MDC1-H2AX interaction is important for the accumulation of other DDR proteins such as Nijmegen breakage syndrome 1 (NBS1), 53BP1 and the activated ATM to the DSBs site, thus amplifying DNA damage signals of G2/M phase checkpoint activation. 53BP1, whose efficient accumulation at sites of DSBs requires H2AX and a functional MDC1-H2AX, subsequently undergoes a notable relocalization to the damage regions following exposure to DSB-inducing IR (10,11). The cell response to DSBs can be characterized by the formation of...