Figure 2.

RNF8-mediated ubiquitination at double-strand breaks. Upon DNA damage, checkpoint kinase ATM phosphorylates H2AX which in turn phosphorylates MDC1 and recruits it to the site of DNA damage. MDC1 then recruits RNF8, the E3 ubiquitin ligase, which conjugates with its E2-conjugating enzyme, Ubc13 to ubiquitinate several variant histones. This leads to the loading of the downstream repair proteins including Abraxas-Brca1-Brcc36 through the ubiquitin interaction domain of RAP80. Brcc36 is a deubiquitinating enzyme, which can deubiquitinate the ubiquitin substrates and reverse this RNF8 pathway.