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S146L in MYC is a context-dependent activating substitution in cancer development
John W Hinds1,2, Edmond J Feris1,2, Owen M Wilkins3
1Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire, Unites States of America.
Plos One
|August 26, 2022
Summary
The MYC oncogene drives tumor growth but is hard to target directly. A specific MYC mutation (S146L) enhances its interaction with a cofactor, potentially increasing cancer activity.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- MYC is a frequently dysregulated oncogene crucial for tumor development.
- Directly targeting MYC for cancer therapy is challenging due to its nature as a transcription factor without enzymatic activity.
- While MYC amplifications and translocations are well-studied, missense mutations remain less understood.
Purpose of the Study:
- To investigate the functional role of a recurrent MYC missense mutation, S146L, in oncogenesis.
- To elucidate the molecular mechanisms by which this mutation contributes to MYC-mediated cancer activity.
Main Methods:
- Characterization of the MYC S146L mutation.
- Analysis of MYC's interaction with its cofactor TRRAP.
- Assessment of MYC's oncogenic activity in relevant cellular contexts.
Main Results:
- The MYC S146L mutation was identified as recurrent.
- This mutation enhances the interaction between MYC and its cofactor TRRAP.
- The enhanced interaction may potentiate oncogenic MYC activity in specific cellular environments.
Conclusions:
- Missense mutations in MYC, like S146L, represent an understudied area with potential implications for cancer therapy.
- Understanding the functional impact of these mutations can reveal novel vulnerabilities in MYC-dependent cancers.
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