RNF168 and RIDDLE syndrome: The importance of RNF8-/RNF168-dependent ubiquitylation is well exemplified by the RIDDLE syndrome, where recessive mutations in the RNF168 gene lead to the expression of aberrant RNF168 protein isoforms, resulting in failure of 53BP1 and BRCA1 accumulation at IR-induced foci and of the subsequent activation of DNA damage responses (Stewart et al., 2009).