p63 and p73 are required for p53-dependent apoptosis in response to DNA damage

Area of Science:

• Molecular Biology
• Cancer Research
• Cellular Biology

Background:

• The tumor-suppressor gene p53 plays a vital role in cellular responses to DNA damage and is frequently mutated in human cancers.
• p53 family members, p63 and p73, are structurally similar to p53 and implicated in apoptosis, but their direct link to tumor suppression is less clear.

Purpose of the Study:

• To investigate the role of p63 and p73 in DNA damage-induced apoptosis, given their structural similarity to p53 and ability to transactivate p53 target genes.
• To determine if p63 and p73 are essential for apoptosis in response to DNA damage, particularly in the context of functional p53.

Main Methods:

• Utilized mouse embryo fibroblasts deficient in one or a combination of p53 family members.
• Employed the adenovirus E1A oncogene to sensitize cells for apoptosis induction and facilitate biochemical analyses.
• Examined p63 and p73 functions using both in vitro (E1A system) and in vivo models where apoptosis is p53-dependent.

Main Results:

• The combined absence of p63 and p73 led to a failure in DNA damage-induced apoptosis.
• This failure occurred even in cells possessing functional p53, indicating a critical role for p63 and p73 beyond p53's direct function.
• Demonstrated that p63 and p73 are essential for initiating apoptosis following DNA damage.

Conclusions:

• p63 and p73 are indispensable for DNA damage-induced apoptosis.
• The loss of both p63 and p73 compromises cellular defense mechanisms against DNA damage, irrespective of p53's functional status.
• These findings reveal a critical cooperative role for the p53 family in maintaining genomic integrity and preventing cancer development.