DNA damage response revisited: the p53 family and its regulators provide endless cancer therapy opportunities

Abstract

Antitumor therapeutic strategies that fundamentally rely on the induction of DNA damage to eradicate and inhibit the growth of cancer cells are integral approaches to cancer therapy. Although DNA-damaging therapies advance the battle with cancer, resistance, and recurrence following treatment are common. Thus, searching for vulnerabilities that facilitate the action of DNA-damaging agents by sensitizing cancer cells is an active research area. Therefore, it is crucial to decipher the detailed molecular events involved in DNA damage responses (DDRs) to DNA-damaging agents in cancer. The tumor suppressor p53 is active at the hub of the DDR. Researchers have identified an increasing number of genes regulated by p53 transcriptional functions that have been shown to be critical direct or indirect mediators of cell fate, cell cycle regulation, and DNA repair. Posttranslational modifications (PTMs) primarily orchestrate and direct the activity of p53 in response to DNA damage. Many molecules mediating PTMs on p53 have been identified. The anticancer potential realized by targeting these molecules has been shown through experiments and clinical trials to sensitize cancer cells to DNA-damaging agents. This review briefly acknowledges the complexity of DDR pathways/networks. We specifically focus on p53 regulators, protein kinases, and E3/E4 ubiquitin ligases and their anticancer potential.

Cancer therapy: Responses to DNA damage

The tumor suppressor protein p53 is at the center of a network of cellular proteins that coordinate responses to DNA damage, and a deeper understanding of this network could reveal new targets for cancer therapy. Commonly called the ‘guardian of the genome’, p53 helps determine whether cells initiate repairs or self-destruct in response to genomic disruption. Mutations affecting p53 play a critical role in determining tumor response to therapy. Researchers led by Roger Leng at the University of Alberta, Edmonton, Canada, have reviewed the various proteins and pathways that interact with p53, and thus inform its ‘decision-making’ process. The development of drugs that affect p53 directly has proven a huge challenge, but these interacting proteins and pathways could offer therapeutic targets. The authors highlight vulnerabilities that could render tumors more susceptible to radiation or chemotherapy.