MDC1

MDC1, or Mediator of DNA Damage Checkpoint 1, is a nuclear protein that functions as a central mediator in the mammalian DNA damage response (DDR). It is recruited to sites of DNA double-strand breaks (DSBs) by recognizing γ-H2AX, the phosphorylated form of H2AX, through its BRCT repeats, enabling MDC1 to spread the DDR signal along chromatin. The N-terminal region contains an FHA domain that participates in protein–phosphopeptide interactions and is a key site for ATM-dependent regulation of MDC1's interactions.

MDC1 acts as a scaffold to amplify DDR signaling. After recruitment, it facilitates retention of ATM at damage foci and promotes the assembly of ubiquitin signaling by recruiting the E3 ligases RNF8 and RNF168 via ATM-phosphorylated MDC1. RNF8 mediates initial histone ubiquitination, which is extended by RNF168, creating binding platforms for downstream effectors such as 53BP1 and BRCA1. This cascade reinforces checkpoint signaling, stabilizes the DNA damage checkpoint, and coordinates repair through homologous recombination and non-homologous end joining.

Deficiency or mutation of MDC1 impairs γ-H2AX foci formation and the recruitment of BRCA1 and 53BP1, compromising checkpoint maintenance and cellular resistance to DNA damage. MDC1 is evolutionarily conserved and operates within the broader DDR network; its expression and function have been studied in relation to cancer biology and responses to radiation and chemotherapeutic agents.