ATM and p53 in aging and cancer: a double-edged sword in genomic integrity.

Abstract

Maintaining genomic stability is essential for detecting DNA damage and activating appropriate responses such as repair, apoptosis, or senescence, primarily mediated by the ATM-p53 axis. ATM is the main sensor of double-strand breaks, and once activated, it will either promote the repair of damaged DNA or eliminate the damaged cells through apoptosis. ATM and p53 mutations upset this equilibrium to cause genomic instability, therapy resistance, and tumor progression in the context of cancer. Oncogene-induced senescence is bypassed by ATM inactivation, which allows cells to progress to become tumors, and p53 mutations allow for uncontrolled proliferation and sensitivity to apoptosis. In addition, persistent ATM signaling can trigger a SASP, which paradoxically further enhances an inflammatory tumor microenvironment and contributes to aging-related diseases and cancer progression. Chemical small molecule p53 activators (PRIMA-1, Nutlin-3) and ATM inhibitors (AZD0156, M4076) sensitize cancer to DNA damaging therapy in cells and nude mice without p53. It remains to be seen whether ATM loss results in ATM/p53 signaling that is always detrimental to tumor proliferation or has context-dependent effects since ATM loss can also promote p53-dependent tumor suppression through senescence and apoptosis in specific cancer types. In this review, we consolidate state-of-the-art findings on ATM and p53 coordination in the processes involved in DNA repair, apoptosis, and senescence to show how ATM and p53 dual involvement in tumor suppression and cancer progression is occurring. It also focuses on therapeutic approaches targeting these pathways to benefit from senescence and intimidating cancer treatment outcomes.