2. Academic Validation
  3. Arginine methylation-dependent METTL14-SMN interaction regulates RNA m6A homeostasis

Arginine methylation-dependent METTL14-SMN interaction regulates RNA m6A homeostasis

  • EMBO Rep. 2025 Oct 6. doi: 10.1038/s44319-025-00590-7.
Yi Zhang 1,  Lei Shen 1,  Lili Ren 2,  Jiangbo Wei 3 4,  Hoang Quoc Hai Pham 1 5,  Xiaoqun Tao 1 5,  Jiamin Guo 5,  Zhihao Wang 1,  Binghui Shen 1,  Rui Su 2,  Chuan He 3 6,  Yanzhong Yang 7 8
Affiliations

Affiliations

  • 1 Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope, Duarte, CA, USA.
  • 2 Department of System Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA.
  • 3 Department of Chemistry, Department of Biochemistry and Molecular Biology, and the Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, 60637, USA.
  • 4 Department of Chemistry and Department of Biological Sciences, National University of Singapore, Singapore, 117544, Singapore.
  • 5 Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, CA, USA.
  • 6 Howard Hughes Medical Institute, University of Chicago, Chicago, IL, 60637, USA.
  • 7 Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope, Duarte, CA, USA. yyang@coh.org.
  • 8 Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, CA, USA. yyang@coh.org.
PMID: 41053315 DOI: 10.1038/s44319-025-00590-7
Abstract

N6-methyladenosine (m6A) homeostasis is essential for development, and its dysregulation is linked to cancers and neurological disorders. However, the mechanisms regulating m6A remain unclear. Here, we identify the survival of motoneuron (SMN) protein as a novel interaction partner of METTL14, a key component of the m6A methyltransferase complex. SMN binds METTL14 via its Tudor domain in an arginine methylation-dependent manner. Mutations in the SMN Tudor domain identified in spinal muscular atrophy (SMA) disrupt its interaction with METTL14 and reduce m6A levels in patient-derived fibroblasts, linking m6A dysregulation to SMA pathology. Both SMN knockdown and SMA mutations impair m6A deposition on the mRNAs of DNA repair genes, mirroring the effects of METTL14 hypomethylation. Consequently, SMA patient fibroblasts are hypersensitive to DNA-damaging agents due to reduced levels of DNA repair gene expression. To explore the function of METTL14 arginine methylation in vivo, we generated a Mettl14 methylation-deficient mouse model (Mettl14RK). Although this model does not show SMA-like phenotypes, the mutants are partially embryonic lethal and show abnormal hematopoiesis, underscoring a role for methylated METTL14 in early development.

Keywords

Arginine Methylation; Genome Stability; Hematopoiesis; METTL14; SMN.

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