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.

Fig. 1. General overview of DNA damage response networks activate by DNA damage.

Once cellular DNA damage occurs, the DDR is activated to protect damaged DNA integrity. The cell cycle is paused to provide cells an opportunity to activate DNA repair mechanisms. When the DNA damage is severe, cell death programs are activated. Dashed arrows indicate altered mechanisms. Alterations in DDR networks may lead to the survival of cells with DNA damage, which eventually may lead to one of the main hallmarks of cancer: genomic instability. This figure was created with BioRender.com (granted a license “Academic License Terms”, No. UP246NTDHZ).

Fig. 2. Simplified schematic showing the activation and deactivation of the p53 network in response to a DNA-damaging agent.

Under stress conditions, such as ionizing radiation (IR), p53 is rapidly stabilized primarily through phosphorylation mediated by different upstream regulators, such as ATM and ATR. Phosphorylated p53 is stabilized mainly through its disassociation from HDM2 and UBE4B; hence, p53 protein accumulates and is translocated into the nucleus. In the nucleus, p53 aggregates as tetramers, the active forms of p53, and transcriptionally activates or suppresses its targeted genes, including cyclin-dependent kinase inhibitor p21 and proapoptotic genes Puma and Bax. Moreover, phosphorylated p53 transcriptionally induces most of its negative regulators, including HDM2, UBE4B, and Wip1, via negative feedback loops. Once DNA damage is resolved or p53 activity is not needed, p53 and most of its negative and positive regulators undergo dephosphorylation by Wip1. Moreover, UBE4B binds and degrades phosphorylated p53. This figure was created using BioRender.com (granted a license “Academic License Terms”, No. BH246NTRVL).