Figure 4.

γ-H2AX is a specific and efficient coordinator of DDR signaling. Following the initial phosphorylation of H2AX by ATM, or DNA-PK, a nucleation reaction is initiated starting with the recruitment of MDC1 and continuing with that of the MRN complex to further activate ATM. This generates a feedback loop that leads to further phosphorylation of H2AX and the chromatin modifications required for the recruitment of 53BP1. The activation cascade culminates with the recruitment of RNF8 to phosphorylated MDC1 and the polyubiquitinylation of H2AX to recruit BRCA1/BARD1 (see text for details).