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. 2019 Mar 9;15(5):909–918. doi: 10.7150/ijbs.31972

Figure 1.

Figure 1

The role of RNF8 involves in DSB signaling pathway. The MRN complex senses the DSB and recruits ATM. Upon being activated by autophosphorylation, ATM phosphorylates histone H2AX (γH2AX). MDC1 recognizes γH2AX and is phosphorylated by ATM and then acts as a platform that recruits RNF8. RNF8 binds CHD4 to decondense chromatin and allow RNF8 to access H2A. RNF8 promotes monoubiquitination of H2A/H2AX with the help of DYRK2. Upon phosphorylation by ATM, L3MBTL2 associates with MDC1 and is polyubiquitinated by RNF8. Ubiquitinated L3MBTL2 recruits RNF168, which amplifies the polyubiquitination chain of H2A/H2AX. After being stabilized by RNF8, JMJD1C facilitates the demethylation and ubiquitination of MDC1. This effect promotes the recognition of RAP80 to ubiquitination signal. Subsequently, BRCA1 complex is recruited to RAP80 via CCDC98 and induces the downstream HR repair by Rad51 through PALB2. The RNF8-UBC13 complex also catalyzes K48 polyubiquitination of JMJD2A. The degradation of JMJD2A promotes the interaction of 53BP1 with methylated H3/H4 and induces NHEJ repair. 53BP1 is also recruited to K15 polyubiquitinated H2A conjugated by RNF8 and RNF168. The RNF8 partner DYRK2 also facilitates the recruitment of 53BP1 to DSB sites.