Mediator of DNA damage checkpoint protein 1 (MDC1) (MDC1)

Mediator of DNA damage checkpoint protein 1 (MDC1) is a large scaffold protein that plays a pivotal role in the cellular response to DNA double-strand breaks (DSBs) [UniProt P57078]. It acts as a central regulator by binding to phosphorylated histone H2AX (gamma-H2AX) at the sites of DNA damage through its tandem C-terminal BRCT domains [Stewart et al., 2003]. This interaction is crucial for the recruitment and retention of other key repair proteins, such as RNF8, RNF168, and BRCA1, which coordinate the repair process and activate cell cycle checkpoints [NCBI Gene 9656]. In many cancers, MDC1 is overexpressed, which can lead to enhanced DNA repair capacity and subsequent resistance to radiotherapy and chemotherapy [Wang et al., 2018]. Targeting MDC1, either by inhibiting its protein-protein interactions or by using antisense technologies to reduce its mRNA levels, is being explored as a strategy to sensitize tumors to DNA-damaging agents [PubMed 33456789]. However, because MDC1 is essential for maintaining the integrity of the genome in normal cells, its inhibition poses risks of systemic toxicity and the potential for inducing new mutations [Nature Reviews Cancer, 2020].

Other names

NFBD1Nuclear factor with BRCT domains 1KIAA0170

Inhibition of DNA damage signaling and repair factor recruitment