Amandine Moretton, Savvas Kourtis, Antoni Gañez Zapater, Chiara Calabrò, Maria Lorena Espinar Calvo, Frédéric Fontaine, Evangelia Darai, Etna Abad Cortel, Samuel Block, Laura Pascual-Reguant, Natalia Pardo-Lorente, Ritobrata Ghose, Matthew G Vander Heiden, Ana Janic, André C Müller, Joanna I Loizou, Sara Sdelci
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引用次数: 0
摘要
虽然细胞新陈代谢会影响 DNA 损伤反应,但人们尚未系统地了解 DNA 损伤修复所需的关键新陈代谢条件。在这里,我们研究了 DNA 损伤修复所必需的代谢酶和过程。通过整合功能基因组学、染色质蛋白质组学和代谢组学,我们详细描述了细胞代谢与 DNA 损伤反应之间的相互作用。进一步分析发现,过氧化物歧化酶1(Peroxiredoxin 1,PRDX1)有助于DNA损伤修复。在DNA损伤应答过程中,PRDX1会转位到细胞核中,在那里它能减少DNA损伤诱导的核活性氧。此外,PRDX1 的缺失会降低天冬氨酸的可用性,而天冬氨酸是 DNA 损伤诱导的从头核苷酸合成上调所必需的。在缺乏 PRDX1 的情况下,细胞会积累复制应激和 DNA 损伤,导致增殖缺陷,而这种缺陷在依托泊苷的作用下会加剧,从而揭示了 PRDX1 作为 DNA 损伤监控因子的作用。
A metabolic map of the DNA damage response identifies PRDX1 in the control of nuclear ROS scavenging and aspartate availability.
While cellular metabolism impacts the DNA damage response, a systematic understanding of the metabolic requirements that are crucial for DNA damage repair has yet to be achieved. Here, we investigate the metabolic enzymes and processes that are essential for the resolution of DNA damage. By integrating functional genomics with chromatin proteomics and metabolomics, we provide a detailed description of the interplay between cellular metabolism and the DNA damage response. Further analysis identified that Peroxiredoxin 1, PRDX1, contributes to the DNA damage repair. During the DNA damage response, PRDX1 translocates to the nucleus where it reduces DNA damage-induced nuclear reactive oxygen species. Moreover, PRDX1 loss lowers aspartate availability, which is required for the DNA damage-induced upregulation of de novo nucleotide synthesis. In the absence of PRDX1, cells accumulate replication stress and DNA damage, leading to proliferation defects that are exacerbated in the presence of etoposide, thus revealing a role for PRDX1 as a DNA damage surveillance factor.
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.