The Mettl3 epitranscriptomic writer amplifies p53 stress responses

Nitin Raj; Mengxiong Wang; Jose A Seoane; Richard L Zhao; Alyssa M Kaiser; Nancie A Moonie; Janos Demeter; Anthony M Boutelle; Craig H Kerr; Abigail S Mulligan; Clare Moffatt; Shelya X Zeng; Hua Lu; Maria Barna; Christina Curtis; Howard Y Chang; Peter K Jackson; Laura D Attardi

doi:10.1016/j.molcel.2022.04.010

The Mettl3 epitranscriptomic writer amplifies p53 stress responses

Mol Cell. 2022 Jul 7;82(13):2370-2384.e10. doi: 10.1016/j.molcel.2022.04.010. Epub 2022 May 4.

Authors

Nitin Raj¹, Mengxiong Wang¹, Jose A Seoane², Richard L Zhao¹, Alyssa M Kaiser¹, Nancie A Moonie³, Janos Demeter³, Anthony M Boutelle¹, Craig H Kerr⁴, Abigail S Mulligan¹, Clare Moffatt¹, Shelya X Zeng⁵, Hua Lu⁵, Maria Barna⁴, Christina Curtis⁶, Howard Y Chang⁷, Peter K Jackson⁸, Laura D Attardi⁹

Affiliations

¹ Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
² Vall d'Hebron Institute of Oncology (VHIO), Barcelona 08035, Spain.
³ Baxter Laboratory, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁴ Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁵ Department of Biochemistry & Molecular Biology, Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA; Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA.
⁶ Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁷ Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94304, USA.
⁸ Baxter Laboratory, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁹ Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: attardi@stanford.edu.

Abstract

The p53 transcription factor drives anti-proliferative gene expression programs in response to diverse stressors, including DNA damage and oncogenic signaling. Here, we seek to uncover new mechanisms through which p53 regulates gene expression using tandem affinity purification/mass spectrometry to identify p53-interacting proteins. This approach identified METTL3, an m⁶A RNA-methyltransferase complex (MTC) constituent, as a p53 interactor. We find that METTL3 promotes p53 protein stabilization and target gene expression in response to DNA damage and oncogenic signals, by both catalytic activity-dependent and independent mechanisms. METTL3 also enhances p53 tumor suppressor activity in in vivo mouse cancer models and human cancer cells. Notably, METTL3 only promotes tumor suppression in the context of intact p53. Analysis of human cancer genome data further supports the notion that the MTC reinforces p53 function in human cancer. Together, these studies reveal a fundamental role for METTL3 in amplifying p53 signaling in response to cellular stress.

Keywords: DNA damage; METTL14; METTL3; N(6)-methyladenosine (m6A) modification; epitranscriptomics; lung cancer; mass spectrometry; methyltransferase complex; p53; tumor suppressor.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinogenesis
Methyltransferases* / metabolism
Mice
RNA
Transcription Factors / metabolism
Tumor Suppressor Protein p53* / genetics

Substances

Transcription Factors
Tumor Suppressor Protein p53
RNA
Methyltransferases
Mettl3 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding