Epigenetic Control of TERRA by FTSJ3 is Critical for Telomerase-Driven Cancers

Price, J. D. W.; Vizeacoumar, F. S.; Abuhussein, O.; Maranda, V.; Zhang, Y.; Adachi, H.; Kyrylenko, L.; Rangel-Pozzo, A.; Dong, H.; Gong, L. H.; Walke, P.; Ganapathysamy, A.; Denomy, C.; Freywald, T.; Dahiya, R.; Elhasasna, H.; Saxena, A.; Vizeacoumar, J.; Patel, H.; Rajamanickam, K.; Nguyen, K.; de Oliveira, D. M.; Lazell-Wright, M.; Morejon-Morales, A.; Aggarwal, A.; Xu, J. L.; Alli, N.; Munhoz, E. P.; Gao, P.; Salsman, J.; Dahiya, D.; Gonzalez-Lopez, C.; Thibault, P. A.; Levin, M.; Dellaire, G.; Jette, N.; Groot, G.; Krishnan, A.; Ahmed, S.; Eskiw, C. H.; Barakat, K.; Wu, Y.; DePinho, R. A.

doi:10.1101/2025.01.26.634101

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bioRxiv · 10.1101/2025.01.26.634101

Epigenetic Control of TERRA by FTSJ3 is Critical for Telomerase-Driven Cancers

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Abstract

Telomerase reverse transcriptase (hTERT) overexpression, a hallmark of most cancers, drives tumorigenesis by enabling limitless replicative potential. Direct targeting of hTERT is challenging, necessitating alternative strategies. Through genome-wide synthetic dosage lethality (SDL) screening in cancer models, including patient-derived organoids, we identify FTSJ3, an RNA 2-O-methyltransferase, as a critical vulnerability in hTERT-overexpressing cells. FTSJ3 methylates telomeric repeat-containing RNA (TERRA), a modification essential for recruiting SUV39H1 to telomeric ends to mediate H3K9 trimethylation and establish stable heterochromatin. Loss of FTSJ3 disrupts this cascade, impairing H3K9 trimethylation, HP1-alpha recruitment, and telomeric heterochromatin maintenance. Notably, this reveals an unexpected dependency on TERRA methylation for telomeric heterochromatin stability in hTERT-driven cancers. Non-malignant cells, lacking telomerase activity and de novo telomere repeat synthesis, are unaffected by FTSJ3 suppression. Our findings establish the FTSJ3/TERRA/SUV39H1 axis as a critical mechanism supporting telomeric heterochromatin stability in hTERT-driven cancers. This telomere-directed epigenetic strategy provides a robust framework for translational therapeutic innovation.

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Price, J. D. W., Vizeacoumar, F. S., Abuhussein, O., Maranda, V., Zhang, Y., Adachi, H., Kyrylenko, L., Rangel-Pozzo, A., Dong, H., Gong, L. H., Walke, P., Ganapathysamy, A., Denomy, C., Freywald, T., Dahiya, R., Elhasasna, H., Saxena, A., Vizeacoumar, J., Patel, H., Rajamanickam, K., Nguyen, K., de Oliveira, D. M., Lazell-Wright, M., Morejon-Morales, A., Aggarwal, A., Xu, J. L., Alli, N., Munhoz, E. P., Gao, P., Salsman, J., Dahiya, D., Gonzalez-Lopez, C., Thibault, P. A., Levin, M., Dellaire, G., Jette, N., Groot, G., Krishnan, A., Ahmed, S., Eskiw, C. H., Barakat, K., Wu, Y., DePinho, R. A.. 2025-01-27. Epigenetic Control of TERRA by FTSJ3 is Critical for Telomerase-Driven Cancers. https://doi.org/10.1101/2025.01.26.634101

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