RNF8 and RIDDLE syndrome: The loss of the RNF168 H2A E3 ligase disrupts histone ubiquitination and causes DNA repair defects and immunodeficiencies associated with RIDDLE syndrome [20]; and RNF8 works in concert with RNF168 to initiate and expand histone ubiquitinations at the Ig loci that resulting in 53BP1 activity and proper class switching [20]–[22].