Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Inserm UMR 1163, Imagine Institute, Paris, France.
Université de Paris, Paris, France.
Life Sci Alliance. 2023 Jun 22;6(9). doi: 10.26508/lsa.202302066. Print 2023 Sep.
The CTP nucleotide is a key precursor of nucleic acids metabolism essential for DNA replication. De novo CTP production relies on CTP synthetases 1 and 2 (CTPS1 and CTPS2) that catalyze the conversion of UTP into CTP. CTP synthetase activity is high in proliferating cells including cancer cells; however, the respective roles of CTPS1 and CTPS2 in cell proliferation are not known. By inactivation of and/or and complementation experiments, we showed that both CTPS1 and CTPS2 are differentially required for cell proliferation. CTPS1 was more efficient in promoting proliferation than CTPS2, in association with a higher intrinsic enzymatic activity that was more resistant to inhibition by 3-deaza-uridine, an UTP analog. The contribution of CTPS2 to cell proliferation was modest when CTPS1 was expressed but essential in absence of CTPS1. Public databases analysis of more than 1,000 inactivated cancer cell lines for CTPS1 or CTPS2 confirmed that cell growth is highly dependent of CTPS1 but less or not of CTPS2. Therefore, our results demonstrate that CTPS1 is the main contributor to cell proliferation.
CTP 核苷酸是核酸代谢的关键前体，对 DNA 复制至关重要。从头合成 CTP 依赖于 CTP 合成酶 1 和 2（CTPS1 和 CTPS2），它们催化 UTP 转化为 CTP。CTP 合成酶活性在包括癌细胞在内的增殖细胞中较高；然而，CTPS1 和 CTPS2 在细胞增殖中的各自作用尚不清楚。通过失活 和/或 以及互补实验，我们表明 CTPS1 和 CTPS2 对细胞增殖都有不同的要求。与对 3-去氮尿苷（UTP 类似物）的抑制更具抗性的更高内在酶活性相关，CTPS1 比 CTPS2 更有效地促进增殖。当表达 CTPS1 时，CTPS2 对细胞增殖的贡献不大，但在缺乏 CTPS1 时则必不可少。对超过 1000 个失活的癌细胞系的公共数据库分析证实，细胞生长高度依赖于 CTPS1，但对 CTPS2 的依赖程度较低或没有。因此，我们的结果表明 CTPS1 是细胞增殖的主要贡献者。
