Multiple roles of ATM in monitoring and maintaining DNA integrity

Abstract

The ability of our cells to maintain genomic integrity is fundamental for protection from cancer development. Central to this process is the ability of cells to recognize and repair DNA damage and progress through the cell cycle in a regulated and orderly manner. In addition, protection of chromosome ends through the proper assembly of telomeres prevents loss of genetic information and aberrant chromosome fusions. Cells derived from patients with ataxia-telangiectasia (A-T) show defects in cell cycle regulation, abnormal responses to DNA breakage, and chromosomal end-to-end fusions. The identification and characterization of the ATM (ataxia-telangiectasia, mutated) gene product has provided an essential tool for researchers in elucidating cellular mechanisms involved in cell cycle control, DNA repair, and chromosomal stability.

Figure 1. PI3KK family members

The PIKK family members have a C-terminal protein kinase doman flanked on either side by an N-terminal FAT domain and a C-terminal FAT-C domain. The N-termini are largely composed of HEAT repeats.

Figure 2. Recruitment of DNA damage response proteins to a DNA double strand break

Prior to DNA damage ATM exists as an inactive dimer. Following the induction of a DNA double strand break, ATM undergoes autophosphorylation producing active ATM monomers. ATM and MRN are rapidly recruited to the site of the DNA double strand break. Upon recruitment, ATM phosphorylates MRE11, NBS1, and H2AX. The phosphorylation of H2AX leads to the recuitment of MDC1. MDC1 is phosphorylated by ATM and phosphorylated MDC1 serves as a docking site recruiting the RING-finger ubiquitin ligase RNF8. RNF8 mono-ubiquitinates γH2AX resulting in the recruitment of 53BP1, BRCA1, and RNF168. The RING-finger ubiquitin ligase RNF168 maintains the ubiquitinated status of γH2AX, aiding in the stabilization 53BP1 and BRCA1 at the break site.