Yan Qingsheng, Ding Jingyi, Khan Sumbul Jawed, Lawton Lee N, Shipp Margaret A
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
iScience. 2023 Mar 17;26(4):106444. doi: 10.1016/j.isci.2023.106444. eCollection 2023 Apr 21.
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.
P53是一种主要的转录调节因子，也是DNA损伤反应（DDR）的效应器，它部分通过与PARP1相互作用定位于DNA损伤位点。然而，在PARP1修饰的DNA损伤位点调节p53丰度和活性的机制仍不明确。含PARP9（BAL1）宏结构域的蛋白质及其伴侣DTX3L（BBAP）E3连接酶会迅速被招募到PARP1-聚腺苷酸化的DNA损伤位点。在初始DDR过程中，我们发现DTX3L迅速与p53共定位，使其富含赖氨酸的C末端结构域多聚泛素化，并将p53靶向蛋白酶体降解。DTX3L基因敲除显著增加并延长了p53在PARP修饰的DNA损伤位点的保留时间。这些发现揭示了DTX3L在初始DDR期间对p53的时空调节中具有非冗余的、PARP和聚腺苷酸化依赖性的作用。我们的研究表明，靶向抑制DTX3L可能通过增加p53的丰度和活性来增强某些DNA损伤剂的疗效。
