精氨酸缺乏通过抑制组蛋白 H4 的翻译和促进 PCNA 泛素化来诱导复制应激并赋予遗传毒性抗性。

Arginine shortage induces replication stress and confers genotoxic resistance by inhibiting histone H4 translation and promoting PCNA ubiquitination.

机构信息

Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.

Irell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA.

出版信息

Cell Rep. 2023 Apr 25;42(4):112296. doi: 10.1016/j.celrep.2023.112296. Epub 2023 Mar 23.

DOI:10.1016/j.celrep.2023.112296

PMID:36961817

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10517088/

Abstract

The arginine dependency of cancer cells creates metabolic vulnerability. In this study, we examine the impact of arginine availability on DNA replication and genotoxicity resistance. Using DNA combing assays, we find that limiting extracellular arginine results in the arrest of cancer cells at S phase and a slowing or stalling of DNA replication. The translation of new histone H4 is arginine dependent and influences DNA replication. Increased proliferating cell nuclear antigen (PCNA) occupancy and helicase-like transcription factor (HLTF)-catalyzed PCNA K63-linked polyubiquitination protect arginine-starved cells from DNA damage. Arginine-deprived cancer cells display tolerance to genotoxicity in a PCNA K63-linked polyubiquitination-dependent manner. Our findings highlight the crucial role of extracellular arginine in nutrient-regulated DNA replication and provide potential avenues for the development of cancer treatments.

摘要

精氨酸依赖性使癌细胞产生代谢脆弱性。在这项研究中，我们研究了精氨酸可用性对 DNA 复制和遗传毒性抗性的影响。通过 DNA 梳理实验，我们发现限制细胞外精氨酸会导致癌细胞在 S 期停滞，并减缓或停止 DNA 复制。新的组蛋白 H4 的翻译依赖于精氨酸，并影响 DNA 复制。增加增殖细胞核抗原 (PCNA) 的占据和解旋酶样转录因子 (HLTF) 催化的 PCNA K63 连接多聚泛素化可保护精氨酸饥饿的细胞免受 DNA 损伤。缺乏精氨酸的癌细胞以 PCNA K63 连接多聚泛素化依赖的方式对遗传毒性具有耐受性。我们的研究结果强调了细胞外精氨酸在营养调节的 DNA 复制中的关键作用，并为癌症治疗的发展提供了潜在途径。