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.

多种肿瘤中尿素循环酶精氨琥珀酸合酶（ASS1）的下调与不良预后相关，部分原因是胞浆天冬氨酸代谢转移用于嘧啶合成，支持由于核苷酸不平衡而导致的增殖和突变。在这里，我们发现 ASS1 的长期缺失会促进 I 型瓜氨酸血症受试者的结肠癌细胞和成纤维细胞中的 DNA 损伤。用阿霉素急性诱导 DNA 损伤后，细胞质和细胞核中 ASS1 的表达升高，且至少具有部分依赖性在第53页； ASS1 通过限制核苷酸合成来代谢抑制细胞质中的细胞周期进程。在细胞核中，ASS1 和 ASL 生成富马酸，用于 SMARCC1 的琥珀化，从而破坏染色质重塑复合物 SMARCC1-SNF5 的稳定性，从而减少基因转录，特别是在 p53 调节的细胞周期基因的子集中。因此，在 DNA 损伤后，ASS1 成为 p53 网络的一部分，可暂停细胞周期进程，从而实现基因组的维持和存活。 ASS1 的缺失会导致 DNA 损伤并促进细胞周期进展，可能导致癌症突变，从而影响适应性潜力。