Specific TP53 mutations impair the recruitment of 53BP1 to DNA double-strand breaks underlying the mechanism of radioresistance.

The tumor suppressor p53, extensively studied for over 40 years, is a key regulator of various cellular pathways, often functioning independently of its transcriptional activity. Notably, p53 has been shown to play a crucial role in DNA repair, not only in sensing DNA damage but also in influencing repair pathway choice. This work assesses the influence of p53 on the recruitment and activity of the NHEJ mediator 53BP1, focusing specifically on common p53 hotspot mutations found in human cancers. The aim is to understand how these mutations impair DNA damage response mechanisms and contribute to genetic instability, which enhances tumor survival. Analysis of p53 missense mutations (R248W, R273C, G245S) revealed mutation-specific effects on 53BP1 and RIF1 recruitment, with G245S retaining wild-type-like 53BP1 recruitment but still exhibiting enhanced BRCA1 foci formation. Given the widespread activation of NHEJ throughout the cell cycle, especially in response to radiotherapy and chemotherapy, gaining insight into how p53 mutations affect this response is vital for developing future therapeutic strategies.