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ASS1 有助于核和胞质 p53 介导的 DNA 损伤反应。

ASS1 metabolically contributes to the nuclear and cytosolic p53-mediated DNA damage response.

机构信息

Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.

Department of Medicine D, Beilinson Hospital, Petah Tikva, Israel.

出版信息

Nat Metab. 2024 Jul;6(7):1294-1309. doi: 10.1038/s42255-024-01060-5. Epub 2024 Jun 10.

Abstract

Downregulation of the urea cycle enzyme argininosuccinate synthase (ASS1) in multiple tumors is associated with a poor prognosis partly because of the metabolic diversion of cytosolic aspartate for pyrimidine synthesis, supporting proliferation and mutagenesis owing to nucleotide imbalance. Here, we find that prolonged loss of ASS1 promotes DNA damage in colon cancer cells and fibroblasts from subjects with citrullinemia type I. Following acute induction of DNA damage with doxorubicin, ASS1 expression is elevated in the cytosol and the nucleus with at least a partial dependency on p53; ASS1 metabolically restrains cell cycle progression in the cytosol by restricting nucleotide synthesis. In the nucleus, ASS1 and ASL generate fumarate for the succination of SMARCC1, destabilizing the chromatin-remodeling complex SMARCC1-SNF5 to decrease gene transcription, specifically in a subset of the p53-regulated cell cycle genes. Thus, following DNA damage, ASS1 is part of the p53 network that pauses cell cycle progression, enabling genome maintenance and survival. Loss of ASS1 contributes to DNA damage and promotes cell cycle progression, likely contributing to cancer mutagenesis and, hence, adaptability potential.

摘要

多种肿瘤中尿素循环酶精氨琥珀酸合成酶(ASS1)的下调与预后不良有关,部分原因是细胞质天冬氨酸用于嘧啶合成的代谢转移,导致核苷酸失衡,从而支持增殖和突变。在这里,我们发现 ASS1 的长期缺失会促进伴瓜氨酸血症 I 型个体的结肠癌细胞和成纤维细胞中的 DNA 损伤。在用阿霉素急性诱导 DNA 损伤后,ASS1 在细胞质和细胞核中的表达水平升高,至少部分依赖于 p53;ASS1 通过限制核苷酸合成在细胞质中限制细胞周期进程。在细胞核中,ASS1 和 ASL 产生富马酸以促进 SMARCC1 的琥珀酰化,使染色质重塑复合物 SMARCC1-SNF5 失稳,从而减少特定于 p53 调节的细胞周期基因子集的基因转录。因此,在 DNA 损伤后,ASS1 是 p53 网络的一部分,该网络会暂停细胞周期进程,从而维持基因组的稳定性和存活。ASS1 的缺失会导致 DNA 损伤并促进细胞周期进程,可能导致癌症的突变和适应性潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96d3/11272581/0067d69af6b9/42255_2024_1060_Fig1_HTML.jpg

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