BiogerontologyMay 5, 2025

ATM and p53 roles in aging and cancer: balancing DNA protection and damage

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 5, 2026

Abstract

ATM and p53 mutations are linked to genomic instability, affecting cancer progression and therapy resistance.

ATM acts as the primary sensor of double-strand DNA breaks and is crucial for activating repair or apoptosis.
Mutations in ATM and p53 disrupt the balance between DNA repair and cell elimination, contributing to cancer development.
Inactivation of ATM allows cells to bypass senescence, leading to tumor formation, while p53 mutations enable unchecked cell growth.
Persistent ATM signaling may lead to an inflammatory tumor microenvironment through a process known as the senescence-associated secretory phenotype (SASP).
Chemical agents that activate p53 or inhibit ATM have shown potential to enhance the effectiveness of DNA-damaging therapies in certain cancer contexts.

Simplified

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.

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ATM and p53 roles in aging and cancer: balancing DNA protection and damage

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