The tumor suppressor p53 plays an important role in the inhibition of cancer progression, particularly in response to chemotherapy or target-specific therapy. Inactivation or mutation of p53 often becomes a cancer’s tactic for drug resistance. One of the clinically applied therapeutic strategies is to inhibit poly(ADP-ribose) polymerase (PARP) activity, as PARP inhibitors are widely used for subsets of tumors with homologous recombination deficiency due to mutation of BRCA1/2 or other DNA repair-associated genes. It has been shown that p53 deficiency or mutation enhances the cytotoxicity of PARP inhibition in various tumors (Williamson et al., 2012). A possible mechanism underlying this is that loss of p53 impairs DNA repair pathways, creating additional tumor vulnerability to PARP inhibition, as wild-type (wt) p53 transcriptionally induces the expression of genes involved in DNA repair (Vousden and Prives, 2009). Alternatively, missense mutant p53 proteins, which comprise the majority of p53 mutations, may interact with replicating DNA in association with PARP to promote aberrant DNA repair, establishing a strong tumor dependency on the PARP-associated repair pathway (Polotskaia et al., 2015; Xiao et al., 2020). However, recent studies also suggested that wt p53 activity may contribute to tumor response to PARP inhibition, including a subset of colorectal cancer (CRC) (Smeby et al., 2020), as PARP inhibitors were found to activate the p53 pathway (Hong et al., 2021). These seemingly contradictory findings warrant the need of further understanding the role of p53 in response to PARP inhibition.