Fig. 7: Model for how UBE2D3 facilitates NHEJ by promoting ATM kinase-dependent DDR activities.

On the one hand UBE2D3 promotes DDR-induced chromatin ubiquitination and 53BP1 recruitment, that are known to be mediated by the RNF8 and RNF168 E3 ligases following ATM kinase activation. 53BP1 is known to promote NHEJ by recruiting the shieldin complex and promoting chromatin mobility (not depicted). Thus, UBE2D3 appears to support the role of RNF168 in promoting NHEJ via chromatin ubiquitination and 53BP1 recruitment. On the other hand, UBE2D3 promotes the ubiquitination and proteasomal degradation of RNF168, thereby preventing RNF168 hyperaccumulation. UBE2D3-deficiency and RNF168 hyperaccumulation are associated with impaired KAP1-S824 phosphorylation, that appears to be in part caused by enhanced phosphatase activity by PP2A, but may also involve other mechanisms. By limiting RNF168 accumulation, UBE2D3 prevents disproportionate dephosphorylation of KAP1 that counteracts the ability of ATM to promote efficient NHEJ through phosphorylation of S824 of KAP1. Thus, this implies the existence of a negative feed-back circuit within ubiquitin and kinase signalling in the DDR that is constrained by UBE2D3 and consists of RNF168- and phosphatase-mediated restriction of ATM-dependent KAP1 phosphorylation.