Abstract
P53 is a master transcriptional regulator and effector of the DNA damage response (DDR) that localizes to DNA damage sites, in part, via an interaction with PARP1. However, the mechanisms that regulate p53 abundance and activity at PARP1-decorated DNA damage sites remain undefined. The PARP9 (BAL1) macrodomain-containing protein and its partner DTX3L (BBAP) E3 ligase are rapidly recruited to PARP1-PARylated DNA damage sites. During an initial DDR, we found that DTX3L rapidly colocalized with p53, polyubiquitylated its lysine-rich C-terminal domain, and targeted p53 for proteasomal degradation. DTX3L knockout significantly increased and prolonged p53 retention at PARP-decorated DNA damage sites. These findings reveal a non-redundant, PARP- and PARylation-dependent role for DTX3L in the spatiotemporal regulation of p53 during an initial DDR. Our studies suggest that targeted inhibition of DTX3L may augment the efficacy of certain DNA-damaging agents by increasing p53 abundance and activity.