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<p>The m<sup>6</sup>A methyltransferase complex (“writer”) regulates mRNA stability and translation, but how its assembly is orchestrated remains incompletely understood. Wilms’ tumor 1-associating protein (WTAP) is a conserved regulatory subunit essential for m<sup>6</sup>A deposition and cell proliferation, yet its structural organization and mechanistic contributions remain elusive. Here, we report that WTAP dimerizes and further assembles into a stable tetramer through its middle coiled-coil domain, as revealed by high-resolution crystal structures. Disruption of this tetrameric interface abolishes WTAP’s interaction with METTL3, METTL14, and ZC3H13, impairs m<sup>6</sup>A deposition, and fails to rescue proliferation defects in WTAP-depleted cells. Live-cell imaging demonstrates that WTAP is required for accurate chromosome segregation, and MeRIP-seq analysis identifies WTAP-dependent m<sup>6</sup>A regulation as a critical determinant sustaining the expression of mitotic regulators, including KIF20A. Together, our study defines a tetrameric scaffold function for WTAP that is essential for writer complex integrity and highlights its pivotal role in linking m<sup>6</sup>A methylation to cell cycle progression.</p>

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WTAP tetramer ensures m6A writer assembly and faithful mitosis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月2日

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  • Shan Zhang,
  • Jin Ye,
  • Manjuan Zhang,
  • Jie Cao,
  • Yujuan Li,
  • Ranran Hu,
  • Da Chen,
  • Ting Li,
  • Jiasheng Chen,
  • Wen Zhu,
  • Wenli Jiang,
  • Jianchao Li,
  • Wei Hu,
  • Jianzhao Liu,
  • Xing Liu,
  • Chao Wang

摘要

The m6A methyltransferase complex (“writer”) regulates mRNA stability and translation, but how its assembly is orchestrated remains incompletely understood. Wilms’ tumor 1-associating protein (WTAP) is a conserved regulatory subunit essential for m6A deposition and cell proliferation, yet its structural organization and mechanistic contributions remain elusive. Here, we report that WTAP dimerizes and further assembles into a stable tetramer through its middle coiled-coil domain, as revealed by high-resolution crystal structures. Disruption of this tetrameric interface abolishes WTAP’s interaction with METTL3, METTL14, and ZC3H13, impairs m6A deposition, and fails to rescue proliferation defects in WTAP-depleted cells. Live-cell imaging demonstrates that WTAP is required for accurate chromosome segregation, and MeRIP-seq analysis identifies WTAP-dependent m6A regulation as a critical determinant sustaining the expression of mitotic regulators, including KIF20A. Together, our study defines a tetrameric scaffold function for WTAP that is essential for writer complex integrity and highlights its pivotal role in linking m6A methylation to cell cycle progression.