2. Academic Validation
  3. Synonymous mutations promote tumorigenesis by disrupting m6A-dependent mRNA metabolism

Synonymous mutations promote tumorigenesis by disrupting m6A-dependent mRNA metabolism

  • Cell. 2025 Feb 11:S0092-8674(25)00095-9. doi: 10.1016/j.cell.2025.01.026.
Yiheng Lan 1,  Zhen Xia 2,  Qizhe Shao 3,  Peng Lin 2,  Jinhong Lu 4,  Xiaoying Xiao 3,  Mengyue Zheng 2,  Di Chen 5,  Yanmei Dou 6,  Qi Xie 7
Affiliations

Affiliations

  • 1 Westlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China; School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China.
  • 2 School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China.
  • 3 Center for Regeneration and Cell Therapy of Zhejiang University, University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China.
  • 4 School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China; Fudan University, Shanghai 200433, China.
  • 5 Center for Regeneration and Cell Therapy of Zhejiang University, University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China. Electronic address: dichen@intl.zju.edu.cn.
  • 6 School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China. Electronic address: douyanmei@westlake.edu.cn.
  • 7 Westlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China; School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China. Electronic address: xieqi@westlake.edu.cn.
PMID: 39952247 DOI: 10.1016/j.cell.2025.01.026
Abstract

Cancer cells acquire numerous mutations during tumorigenesis, including synonymous mutations that do not change the amino acid sequence of a protein. RNA N6-methyladenosine (m6A) is a post-transcriptional modification that plays critical roles in oncogenesis. Herein, we identified 12,849 mutations in the Cancer genome with the potential to perturb m6A modification patterns, which we refer to as "m6A disruption mutations (m6A-DMs)." These are either synonymous m6A-DMs (sm6A-DMs) or missense m6A-DMs (mm6A-DMs) mutations, and the former is enriched within tumor suppressor genes, such as CDKN2A and BRCA2. Using epitranscriptomic editing, we demonstrate that manipulating m6A levels at specific sm6A-DM sites influences mRNA stability. Furthermore, introducing CDKN2A sm6A-DMs into Cancer cells promotes tumor growth while BRCA2 sm6A-DMs sensitize tumors to the poly (ADP-ribose) polymerase inhibitor (PARPi) treatment. Our findings demonstrate sm6A-DMs as potential oncogenic drivers, unveiling implications for synonymous mutations in tumorigenesis and beyond.

Keywords

cancer; epitranscriptomic; m(6)A; m(6)A-DMs; sm(6)A-DMs; synonymous mutation; tumor suppressor gene.

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