Dppa2 synergizes with p53 in promoting DNA damage-induced apoptosis of mouse embryonic stem cells [ChIP-Seq]

Dppa2 (Developmental pluripotency associated 2), specifically expressed in embryonic stem cells (ESCs) and reactivated in certain cancers, plays important roles in regulating the transition between pluripotency and differentiation. However, its involvement in the DNA damage response (DDR) of mouse ESCs (mESCs) has remained unclear. Here, we identify a surprising pro-apoptotic function for Dppa2 as a novel p53-interacting partner in mESCs. Dppa2 physically interacts with p53 and is transcriptionally repressed by p53 upon DNA damage. By comparing the effects of Dppa2 in p53+/+ and p53-/- mESCs, we find that Dppa2 promotes DNA damage-induced apoptosis (DIA) of mESCs in a p53-dependent manner. RNA-seq and chromatin immunoprecipitation followed by sequencing (ChIP-seq) reveal that Dppa2 and p53 co-repress genes involved in cell cycle regulation and self-renewal, which are highly expressed in ESCs. Mechanistically, Dppa2 recruits p53 to the enhancers of these co-repressed genes. Consequently, Dppa2 depletion significantly compromises p53’s binding intensity and alleviates transcriptional repression. Collectively, our findings uncover a novel mechanism of p53-mediated apoptosis achieved through cooperation with its ESC-specific partner, Dppa2, thereby highlighting a previously unappreciated tumor suppressor identity of Dppa2. To explore Dppa2 binding sites in mESCs upon DNA damage, we performed Dppa2 ChIP-seq on p53+/+ R1E cells, either untreated or treated with Adriamycin for 8 h.