ATM phosphorylates MDC1

The function of MDC1 in recruiting and retaining DNA repair proteins at the sites of DNA damage (Xu and Stern 2003, Stewart et al. 2003) is promoted by the ATM-mediated phosphorylation of MDC1 (Liu et al. 2012). Phosphorylation of MDC1 (NFBD1) by ATM at threonine residue T4 stabilizes otherwise unstable MDC1 homodimers by enabling in trans interaction of MDC1 FHA domains with phosphorylated N-terminal threonine residues (Goldberg et al. 2003, Liu et al. 2012). ATM also phosphorylates MDC1 on at least four threonine residues that match the consensus RNF8-binding sequence T-Q-X-F: T699, T719, T752, T765 (Kolas et al. 2007). Binding of the ubiquitin ligase RNF8 to ATM phosphorylated MDC1 is necessary for the recruitment of TP53BP1 and BRCA1 to DNA double-strand break (DSB) sites.

MDC1（核因子NFBD1）在DNA损伤位点招募并保留DNA修复蛋白的功能（Xu和Stern 2003，Stewart等2003），此功能得到ATM介导的MDC1磷酸化（Liu等2012）的促进作用。ATM通过在苏氨酸残基T4处磷酸化MDC1，使原本不稳定的MDC1同源二聚体得以稳定，从而实现MDC1 FHA结构域与磷酸化N端苏氨酸残基的跨结构域相互作用（Goldberg等2003，Liu等2012）。ATM还至少在四个苏氨酸残基（T699、T719、T752、T765）上磷酸化MDC1，这些残基与RNF8结合位点的一致性序列T-Q-X-F相匹配（Kolas等2007）。RNF8泛素连接酶与ATM磷酸化MDC1的结合对于TP53BP1和BRCA1招募至DNA双链断裂（DSB）位点至关重要。