A. DNA double-stranded breaks form free DNA ends. B. Free DNA ends are detected by the MRN complex, which recruits ATM kinase to phosphorylate H2AX to form γ-H2AX. C. MDC1 interacts directly with γ-H2AX to recruit additional MRN complex and ATM, amplifying the γ-H2AX signal. It also recruits RNF8, resulting in the ubiquitination of γ-H2AX. D. In the absence of MDC1, free ends are still detected by the MRN complex, but the γ-H2AX signal is not propagated onto nearby chromatin to form visible γ-H2AX foci.