Fagherazzi Paolo, Stixová Lenka, Bartova Eva
Department of Cell Biology & Epigenetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic.
Eur Biophys J. 2025 Jul 14. doi: 10.1007/s00249-025-01774-8.
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.
肿瘤抑制因子p53已被广泛研究40多年，是各种细胞通路的关键调节因子，其功能通常独立于转录活性。值得注意的是，p53已被证明在DNA修复中起关键作用，不仅能感知DNA损伤，还能影响修复途径的选择。这项工作评估了p53对NHEJ介质53BP1募集和活性的影响，特别关注人类癌症中常见的p53热点突变。目的是了解这些突变如何损害DNA损伤反应机制并导致基因不稳定，从而提高肿瘤存活率。对p53错义突变（R248W、R273C、G245S）的分析揭示了对53BP1和RIF1募集的突变特异性影响，其中G245S保留了野生型样的53BP1募集，但仍表现出增强的BRCA1灶形成。鉴于NHEJ在整个细胞周期中广泛激活，尤其是对放疗和化疗的反应，深入了解p53突变如何影响这种反应对于制定未来的治疗策略至关重要。
