Abstract
Repair of double-stranded breaks (DSBs) is vital to maintaining genomic stability. In mammalian cells, DSBs are resolved in one of the following complex repair pathways: nonhomologous end-joining (NHEJ), homologous recombination (HR), or the inclusive DNA damage response (DDR). These repair pathways rely on factors that utilize reversible phosphorylation of proteins as molecular switches to regulate DNA repair. Many of these molecular switches overlap and play key roles in multiple pathways. For example, the NHEJ pathway and the DDR both utilize DNA-PK phosphorylation, whereas the HR pathway mediates repair with phosphorylation of RPA2, BRCA1, and BRCA2. Also, the DDR pathway utilizes the kinases ATM and ATR, as well as the phosphorylation of H2AX and MDC1. Together, these molecular switches regulate repair of DSBs by aiding in DSB recognition, pathway initiation, recruitment of repair factors, and the maintenance of repair mechanisms.
Highlights
The eukaryotic genome is under constant mutational stress through exposure to exogenous and endogenous agents that damage DNA
H2AX is at the center of cellular responses to DNA double-stranded breaks (DSBs)
In response to DNA damage, H2AX is phosphorylated on a conserved serine residue at the carboxyl terminus by PIKK family, including Ataxia Telangiectasia-Mutated (ATM), ATR, and DNA-PKcs
Summary
These external and internal factors damage DNA introducing a wide variety of genetic alterations including: deletions, translocations, and chromosome loss, which can result in cell death. The NHEJ pathway occurs mainly in the G0 and G1 phase of the cell cycle by joining DSB ends directly or after limited processing, whereas HR uses a sister homolog as a template for repair during late S and G2 phases [5]. Encompassing these repair pathways, mammalian cells possess a DNA damage response (DDR). The mechanism of reversible phosphorylation in proteins is an important regulatory mechanism for DNA repair pathways
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