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

Area of Science:

• Genomic stability and DNA damage response.
• Cancer biology and tumor progression.
• Cellular senescence and apoptosis.

Background:

• Genomic stability is crucial, involving DNA damage detection and response pathways like ATM-p53.
• ATM (Ataxia-Telangiectasia Mutated) and p53 are key regulators of DNA repair, apoptosis, and senescence.
• Mutations in ATM or p53 disrupt these processes, leading to genomic instability, cancer, and therapy resistance.

Purpose of the Study:

• To review the dual role of ATM and p53 in tumor suppression and cancer progression.
• To consolidate findings on ATM-p53 coordination in DNA repair, apoptosis, and senescence.
• To highlight therapeutic strategies targeting the ATM-p53 pathway for cancer treatment.

Main Methods:

• Literature review of state-of-the-art findings on ATM and p53.
• Analysis of ATM-p53 signaling in DNA repair, apoptosis, and senescence.
• Examination of therapeutic approaches targeting ATM and p53.

Main Results:

• ATM inactivation bypasses oncogene-induced senescence, promoting tumor formation.
• p53 mutations drive uncontrolled proliferation and resistance to apoptosis.
• Persistent ATM signaling can induce a senescence-associated secretory phenotype (SASP), enhancing inflammation and cancer progression.
• Small molecule ATM inhibitors and p53 activators sensitize cancer to DNA-damaging therapies.
• The precise role of ATM loss in tumor proliferation may be context-dependent, potentially promoting tumor suppression in some cancers.

Conclusions:

• The ATM-p53 axis has a complex, context-dependent role in both tumor suppression and cancer progression.
• Understanding ATM-p53 coordination is vital for developing effective cancer therapies.
• Targeting ATM and p53 pathways offers promising strategies to enhance cancer treatment outcomes by leveraging senescence and apoptosis.