- The MRN complex recognizes and binds the free ends of the DNA
- ATM is recruited to the foci
- ATM phosphorylates H2AX, Chk2 and p53
- Chk2 phosphorylates CDC25
- Cell cycle is arrested and chromatin opens for DNA repair
Several diseases are associated with defects in the DSB response pathway. Among them are ataxia-telangiectasia, resulting from mutations in ATM. Several mutations in ATM will result in the A-T phenotype, and approximately 1% of the population carries one mutated allele. Those that suffer from this syndrome show immunodeficiency and increased cancer rates, and they have a life expectancy of 17-23 years. In addition to A-T, Nijimegen breakage syndrome results from mutations in Nbs1, and A-T like disorder (ATLD) results from Mre11 mutations. Breast cancer may also have connections to DSB repair, as BRCA1 is associated with the BASC complex, which is involved in this and many other pathways for DNA repair. BRCA1 acts as an ATM substrate and localizes to IRIFs, possibly acting as a scaffold.