PRPS2 enhances RNA m6A methylation by stimulating SAM synthesis through enzyme-dependent and independent mechanisms

Lin Zhang, Xian Zhao, Jingyan Hu, Tingting Li, Hong-Zhuan Chen, Ao Zhang, Hao Wang (), Jianxiu Yu () and Liang Zhang ()
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Lin Zhang: Shanghai Jiao Tong University
Xian Zhao: Shanghai Jiao Tong University School of Medicine
Jingyan Hu: Shanghai Jiao Tong University
Tingting Li: Shanghai Jiao Tong University
Hong-Zhuan Chen: Shanghai University of Traditional Chinese Medicine
Ao Zhang: Shanghai Jiao Tong University
Hao Wang: Fudan University
Jianxiu Yu: Shanghai Jiao Tong University School of Medicine
Liang Zhang: Shanghai Jiao Tong University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Cancer cells exploit altered metabolic pathways to dynamically regulate epigenetic methylation and thus promote tumorigenesis and metastasis. In various human cancers, such as lung adenocarcinoma, the level of a key cellular metabolite, S-adenosylmethionine (SAM), is prominently upregulated for RNA hypermethylation as the methyl donor. However, the specific mechanisms by which cancer cells produce SAM to sustain RNA methylation remain elusive. Here, we demonstrate that PRPS2, a phosphoribosyl pyrophosphate synthetase isoform involved in the first and rate-limiting step of the purine biosynthesis pathway, exhibits distinct oncogenic functionality in regulating RNA methylation, unlike its homolog PRPS1. PRPS2 utilizes four non-conserved key residues to bypass the typical ADP/GDP allosteric feedback inhibition, enabling sustained excess production of newly synthesized ATP. Moreover, PRPS2 stabilizes methionine adenosyltransferase 2 A (MAT2A) through direct interactions to positively stimulate ATP utilization and SAM synthesis for RNA m6A specific methylation via the WTAP/METTL3/METTL14 methyltransferase complex, thereby promoting lung tumorigenesis. Our study links nucleotide biosynthesis with RNA epigenetics in cancer progression through the PRPS2-MAT2A-WTAP/METTL3/METTL14 axis, and elucidates both enzyme-dependent and independent functions of PRPS2. These findings have significant implications for developing targeted therapies for cancers associated with PRPS2 abnormalities.

Date: 2025
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DOI: 10.1038/s41467-025-59119-0

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