METTL3 promotes homologous recombination repair and modulates chemotherapeutic response in breast cancer by regulating the EGF/Rad51 axis
- Nanjing Normal University, China
Abstract
METTL3 and N6-methyladenosine (m6A) are involved in many types of biological and pathological processes, including DNA repair. However, the function and mechanism of METTL3 in DNA repair and chemotherapeutic response remain largely unknown. In present study, we identified that METTL3 participates in the regulation of homologous recombination repair (HR), which further influences chemotherapeutic response in both MCF-7 and MDA-MB-231 breast cancer (BC) cells. Knockdown of METTL3 sensitized these BC cells to Adriamycin (ADR; also named as doxorubicin) treatment and increased accumulation of DNA damage. Mechanically, we demonstrated that inhibition of METTL3 impaired HR efficiency and increased ADR-induced DNA damage by regulating m6A modification of EGF/RAD51 axis. METTL3 promoted EGF expression through m6A modification, which further upregulated RAD51 expression, resulting in enhanced HR activity. We further demonstrated that the m6A 'reader', YTHDC1, bound to the m6A modified EGF transcript and promoted EGF synthesis, which enhanced HR and cell survival during ADR treatment in breast cancer cells. Our findings reveal a pivotal mechanism of METTL3-mediated HR and chemotherapeutic drug response, which may contribute to cancer therapy.
Data availability
The raw sequencing data were deposited in the Gene Expression Omnibus database (accession to cite for these SRA data: PRJNA743152)
Article and author information
Author details
Funding
National Natural Science Foundation of China (32171407)
- Zhigang Hu
National Natural Science Foundation of China (81872284)
- Zhigang Guo
Natural Science Fund of Colleges and Universities in Jiangsu Province (19KJA180010)
- Zhigang Hu
Priority Academic Program Development of Jiangsu Higher Education Institutions
- Zhigang Guo
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Maria Spies, University of Iowa, United States
Ethics
Animal experimentation: All animal experiments were performed according to the procedures approved by the Laboratory Animal Care Committee at Nanjing Normal University (Permit number IACUC-20210251) and followed National Institutes of Health guide for the care and use of Laboratory animals.
Version history
- Received: November 3, 2021
- Preprint posted: November 12, 2021 (view preprint)
- Accepted: April 29, 2022
- Accepted Manuscript published: May 3, 2022 (version 1)
- Version of Record published: May 11, 2022 (version 2)
Copyright
© 2022, Li et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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METTL3 promotes homologous recombination repair and modulates chemotherapeutic response in breast cancer by regulating the EGF/Rad51 axis
eLife 11:e75231.
https://doi.org/10.7554/eLife.75231
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