PDF(Pubmed)
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酸琥珀酸合酶（ASS1）的下调与预后不良有关，部分原因是由于胞质天冬氨酸代谢转移用于嘧啶合成，由于核苷酸失衡，支持增殖和诱变。这里,我们发现ASS1的长期丢失会促进I型瓜氨酸血症患者结肠癌细胞和成纤维细胞的DNA损伤。ASS1在胞质溶胶和细胞核中的表达升高，至少部分依赖于p53；ASS1通过限制核苷酸合成来代谢地限制胞质溶胶中的细胞周期进程。在细胞核中，ASS1和ASL产生富马酸用于SMARCC1的琥珀酸，使染色质重塑复合物SMARCC1-SNF5不稳定以降低基因转录，特别是在p53调节的细胞周期基因的一个子集。因此，DNA损伤后,ASS1是暂停细胞周期进程的p53网络的一部分，使基因组得以维持和生存。ASS1的缺失有助于DNA损伤并促进细胞周期进程，可能导致癌症诱变，因此，适应性潜力。
