p53 orchestrates DNA replication restart homeostasis by suppressing mutagenic RAD52 and POLθ pathways

Area of Science:

• Molecular Biology
• Genetics
• Cancer Research

Background:

• The p53 tumor suppressor is classically known for its roles in transcription, apoptosis, and cell cycle arrest.
• Replication-mediated genomic instability is a key factor in oncogenesis, and p53 mutations are linked to tumor progression and drug resistance.

Purpose of the Study:

• To investigate the role of p53 in DNA replication fork stability and genomic integrity.
• To understand the mechanisms by which p53 mutations contribute to cancer progression and drug resistance.

Main Methods:

• Analysis of human and murine separation-of-function p53 alleles.
• Assaying protein-DNA fork interactions in single cells.
• Examination of patient-derived mutational signatures.

Main Results:

• p53 null and gain-of-function mutations impair the restart of stalled or damaged DNA replication forks, leading to genomic instability.
• p53 facilitates the recruitment of the MRE11 nuclease to replication forks via interaction with MLL3.
• p53 deficiency allows mutagenic RAD52 and POLθ pathways to inappropriately engage with stalled replication forks, as observed in breast cancer mutational signatures.

Conclusions:

• p53 acts as a crucial regulator of replication homeostasis within a DNA replication restart network.
• p53's role in suppressing replication-associated genomic instability has significant implications for cancer therapy resistance.
• This study defines a novel function for p53 in maintaining genome stability beyond its canonical roles.