Figure 3: Phosphorylation events in DDR. Key factors in the DDR regulate via a series of phosphorylation events. Members of the PIKK family (ATM, ATR, and DNA-PK) are first to the DNA damage site and phosphorylate histone H2AX. As previously mentioned, DNA-PK is also a critical kinase in the NHEJ pathway. Phosphorylated H2AX recruits and phosphorylates Mediator of Damage Checkpoint protein 1 (MDC1). Once phosphorylated MDC1 then serves as a platform for further recruitment of DDR factors, including the MRN complex and RNF8. RNF8 then ubiquitinates histones and downstream recruits BRCA1, 53BP1, and RAP80.