全基因组 CRISPR 筛选确定了野生型和突变型 p53 稳定性的新型调节器。

IF 8.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Systems Biology Pub Date : 2024-06-01 Epub Date: 2024-04-05 DOI:10.1038/s44320-024-00032-x
YiQing Lü, Tiffany Cho, Saptaparna Mukherjee, Carmen Florencia Suarez, Nicolas S Gonzalez-Foutel, Ahmad Malik, Sebastien Martinez, Dzana Dervovic, Robin Hyunseo Oh, Ellen Langille, Khalid N Al-Zahrani, Lisa Hoeg, Zhen Yuan Lin, Ricky Tsai, Geraldine Mbamalu, Varda Rotter, Patricia Ashton-Prolla, Jason Moffat, Lucia Beatriz Chemes, Anne-Claude Gingras, Moshe Oren, Daniel Durocher, Daniel Schramek
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引用次数: 0

摘要

肿瘤抑制因子 p53(TP53)在癌症中经常发生突变,这通常不仅会导致其抑制肿瘤的功能丧失,而且还会获得显性阴性甚至致癌的功能增益特性。野生型 p53 水平受到严格调控,而突变体通常在肿瘤中保持稳定,这对其致癌特性至关重要。在这里,我们利用基于标记的全基因组CRISPR筛选系统地分析了调控野生型和突变型p53蛋白稳定性的因素。野生型 p53 的大多数调控因子也能调控 p53 突变体,但 p53 R337H 的调控因子除外,它们在很大程度上只调控该突变体。从机理上讲,FBXO42 是 p53 突变体亚群的正调控因子,它与 CCDC6 一起控制 USP28 介导的突变体 p53 稳定。此外,C16orf72/HAPSTR1 对野生型 p53 和所有测试的突变体都有负向调节作用。C16orf72/HAPSTR1 通常在乳腺癌中扩增,它的过表达会降低小鼠乳腺上皮细胞中 p53 的水平,导致乳腺癌的加速发生。这项研究为 p53 的稳定性调控提供了一个网络视角,有可能为在癌症中加强野生型 p53 或靶向突变型 p53 的策略提供指导。
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Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability.

Tumor suppressor p53 (TP53) is frequently mutated in cancer, often resulting not only in loss of its tumor-suppressive function but also acquisition of dominant-negative and even oncogenic gain-of-function traits. While wild-type p53 levels are tightly regulated, mutants are typically stabilized in tumors, which is crucial for their oncogenic properties. Here, we systematically profiled the factors that regulate protein stability of wild-type and mutant p53 using marker-based genome-wide CRISPR screens. Most regulators of wild-type p53 also regulate p53 mutants, except for p53 R337H regulators, which are largely private to this mutant. Mechanistically, FBXO42 emerged as a positive regulator for a subset of p53 mutants, working with CCDC6 to control USP28-mediated mutant p53 stabilization. Additionally, C16orf72/HAPSTR1 negatively regulates both wild-type p53 and all tested mutants. C16orf72/HAPSTR1 is commonly amplified in breast cancer, and its overexpression reduces p53 levels in mouse mammary epithelium leading to accelerated breast cancer. This study offers a network perspective on p53 stability regulation, potentially guiding strategies to reinforce wild-type p53 or target mutant p53 in cancer.

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来源期刊
Molecular Systems Biology
Molecular Systems Biology 生物-生化与分子生物学
CiteScore
18.50
自引率
1.00%
发文量
62
审稿时长
6-12 weeks
期刊介绍: Systems biology is a field that aims to understand complex biological systems by studying their components and how they interact. It is an integrative discipline that seeks to explain the properties and behavior of these systems. Molecular Systems Biology is a scholarly journal that publishes top-notch research in the areas of systems biology, synthetic biology, and systems medicine. It is an open access journal, meaning that its content is freely available to readers, and it is peer-reviewed to ensure the quality of the published work.
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