Metallothionein loss in cancer cells contributes to increased mutations through defective DNA repair and metabolic imbalance

Mina-Abouda, M.; Rees, A. C.; Evans, D.; Villamor, E.; Fullbright, G.; Ghent, H. R.; Clark, M. A.; Zhang, W. Y.; Koehler, I.; Berry, I.; Oesch, S.; Hutchinson, R.; Delisi, D.; de Solis, C.; Maslov, A. Y.; Bradley, C.; Sharifi, S.; Acero, R. E. P.; Peterson, Y. K.; Zhang, J.; Ye, Z.; Rodrick, T. C.; Townsend, D. M.; Gentile, S.; Orr, B.; Jones, D.; Hartman, J. H.; Long, D. T.; Sczepanski, J. T.; Delaney, J. R.

doi:10.64898/2026.07.06.736843

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bioRxiv · 10.64898/2026.07.06.736843

Metallothionein loss in cancer cells contributes to increased mutations through defective DNA repair and metabolic imbalance

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Abstract

Understanding which genes are involved in mutagenesis is essential for developing cancer prevention and treatment strategies; establishing protectors of the genome has revolutionized cancer biology. Here, we describe metallothionein (MT) proteins as previously uncharacterized protectors against mutagenesis. MT is a heavy metal binding protein essential for zinc homeostasis and protection against heavy metal cytotoxicity. Because zinc binds approximately 10-15% of the proteome and is critical for processes such as DNA repair and mitochondrial health, MT loss is expected to disrupt these processes. We hypothesized that MT loss induces genomic instability by impairing DNA repair and mitochondrial function. In this study, the consequences of MT deficiency in high-grade serous ovarian cancer (HGSC) were investigated by knockdown of the most highly expressed MT, MT2A. Loss of MT2A resulted in the impaired DNA repair pathway base excision repair (BER), leading to increased mutagenesis. MT2A deficiency produced mitochondrial dysfunction, characterized by a decrease in mitochondrial membrane potential, glycolysis, oxidative phosphorylation, amino acids, and an imbalance of nucleobases. Together, these defects reflect cellular states associated with increased cancer aggressiveness. These findings identify MT as a fundamental hub maintaining genomic and metabolic integrity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=84 SRC="FIGDIR/small/736843v2_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@1af4adeorg.highwire.dtl.DTLVardef@15c588forg.highwire.dtl.DTLVardef@1ba5181org.highwire.dtl.DTLVardef@13d150b_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Mina-Abouda, M., Rees, A. C., Evans, D., Villamor, E., Fullbright, G., Ghent, H. R., Clark, M. A., Zhang, W. Y., Koehler, I., Berry, I., Oesch, S., Hutchinson, R., Delisi, D., de Solis, C., Maslov, A. Y., Bradley, C., Sharifi, S., Acero, R. E. P., Peterson, Y. K., Zhang, J., Ye, Z., Rodrick, T. C., Townsend, D. M., Gentile, S., Orr, B., Jones, D., Hartman, J. H., Long, D. T., Sczepanski, J. T., Delaney, J. R.. 2026-07-07. Metallothionein loss in cancer cells contributes to increased mutations through defective DNA repair and metabolic imbalance. https://doi.org/10.64898/2026.07.06.736843

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