p53 gain-of-function cancer mutants induce genetic instability by inactivating ATM

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• TP53 is the most frequently mutated tumor suppressor gene in human cancers.
• Certain TP53 missense mutations acquire novel oncogenic activities beyond loss of tumor suppression.

Purpose of the Study:

• To investigate the gain-of-function mechanisms of common p53 cancer mutations (R248W and R273H).
• To elucidate how these mutant p53 proteins promote tumorigenesis through disruption of DNA damage response pathways.

Main Methods:

• Introduction of common p53 cancer mutations (R248W, R273H) into the humanized p53 knock-in (HUPKI) mouse model.
• Assessment of tumor suppressor function loss, oncogenic activities, genetic instability (interchromosomal translocations), and cell cycle checkpoint function (G2-M checkpoint) in p53-mutant mice and cells.
• Investigation of molecular interactions between p53 mutants, Mre11, and the MRN complex, and their impact on ATM activation following DNA double-stranded breaks (DSBs).

Main Results:

• p53-mutant mice exhibited abolished tumor suppressor functions and rapid onset of specific cancers.
• Increased interchromosomal translocations were detected in pre-tumor thymocytes of p53-mutant mice.
• The G2-M checkpoint was impaired in p53-mutant cells post-DNA damage, unlike in p53(-/-) cells.
• p53 mutants interacted with Mre11, hindering MRN complex binding to DSBs and impairing ATM activation.

Conclusions:

• p53 gain-of-function mutants promote tumorigenesis through a novel mechanism.
• This mechanism involves active disruption of critical DNA damage response pathways, including ATM signaling.
• Understanding these oncogenic properties of mutant p53 is crucial for developing targeted cancer therapies.