A metabolic map of the DNA damage response identifies PRDX1 in the control of nuclear ROS scavenging and aspartate availability.
A metabolic map of the DNA damage response identifies PRDX1 in the control of nuclear ROS scavenging and aspartate availability.
复制标题
DNA损伤反应的代谢图可以确定核ROS清除和天冬氨酸可用性的PRDX1。
DOI：
10.15252/msb.202211267
复制
发表时间：
2023-07-11
影响因子：
9.9
通讯作者：
中科院分区：
文献类型：
--
作者：
虽然细胞代谢影响DNA损伤反应，但对DNA损伤修复至关重要的代谢要求的系统理解尚未实现。在这里，我们调查的代谢酶和过程是必不可少的DNA损伤的决议。通过整合功能基因组学与染色质蛋白质组学和代谢组学，我们提供了细胞代谢和DNA损伤反应之间的相互作用的详细描述。进一步的分析表明，Peroxiredoxin 1，PRDX 1，有助于DNA损伤修复。在DNA损伤反应期间，PRDX 1易位到细胞核，在那里它减少DNA损伤诱导的核活性氧。此外，PRDX 1缺失降低了天冬氨酸的可用性，这是DNA损伤诱导的从头核苷酸合成上调所必需的。在没有PRDX 1的情况下，细胞积累复制应激和DNA损伤，导致在依托泊苷存在下加剧的增殖缺陷，从而揭示了PRDX 1作为DNA损伤监视因子的作用。遗传筛选，蛋白质组学和代谢组学进行研究代谢和DNA损伤反应之间的串扰。综合分析将Peroxiredoxin-1（PRDX 1）确定为DNA损伤监测因子。
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. Genetic screens, proteomics, and metabolomics are performed to investigate the crosstalk between metabolism and the DNA damage response. Integrative analyses identify Peroxiredoxin‐1 (PRDX1) as a DNA damage surveillance factor.