Constant Activation of DNA Damage Response May Lead to Build-Up of Mutant p53 by Changing How p53 Is Tagged for Breakdown

High-level mutant p53 expression in lung cancer cells is associated with preferential p53 monoubiquitination.

• Mutant p53 proteins have an abnormally long half-life and increased abundance compared to wild-type p53 in tumors.
• DNA damage checkpoint activation is linked to the maintenance of mutant p53 levels in cancer.
• The regulation of mutant p53 ubiquitination status is influenced by ataxia-telangiectasia mutated (ATM) activation and phosphorylation of mutant p53 at serine 15.
• Inhibition of ATM or mutation of serine 15 restores polyubiquitination of mutant p53, suggesting a regulatory mechanism.
• Caffeine treatment rescues MDM2-dependent degradation of mutant p53 in cells with active DNA damage signaling.
• Cells with the highest levels of DNA damage response show the greatest p53 levels, indicating a connection between DNA damage signaling and mutant p53 abundance.

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