Genome-wide screens identify specific drivers of mutant hTERT promoters

Page view(s)
3
Checked on Apr 14, 2022
Genome-wide screens identify specific drivers of mutant hTERT promoters
Title:
Genome-wide screens identify specific drivers of mutant hTERT promoters
Other Titles:
Proceedings of the National Academy of Sciences
Publication Date:
18 January 2022
Citation:
Shanmugam, Ozturk, M. B., Low, J.-L., Akincilar, S. C., Chua, J. Y. H., Thangavelu, M. T., Periyasamy, G., DasGupta, R., & Tergaonkar, V. (2022). Genome-wide screens identify specific drivers of mutant hTERT promoters. Proceedings of the National Academy of Sciences, 119(3), e2105171119. https://doi.org/10.1073/pnas.2105171119
Abstract:
Cancer-specific hTERT promoter mutations reported in 19% of cancers result in enhanced telomerase activity. Understanding the distinctions between transcriptional regulation of wild-type (WT) and mutant (Mut) hTERT promoters may open up avenues for development of inhibitors which specially block hTERT expression in cancer cells. To comprehensively identify physiological regulators of WT- or Mut-hTERT promoters, we generated several isogenic reporter cells driven by endogenous hTERT loci. Genome-wide CRISPR-Cas9 and small interfering RNA screens using these isogenic reporter lines identified specific regulators of Mut-hTERT promoters. We validate and characterize one of these hits, namely, MED12, a kinase subunit of mediator complex. We demonstrate that MED12 specifically drives expression of hTERT from the Mut-hTERT promoter by mediating long-range chromatin interaction between the proximal Mut-hTERT promoter and T-INT1 distal regulatory region 260 kb upstream. Several hits identified in our screens could serve as potential therapeutic targets, inhibition of which may specifically block Mut-hTERT promoter driven telomerase reactivation in cancers.
License type:
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Funding Info:
This research / project is supported by the National Research Foundation - Competitive Research Programme
Grant Reference no. : NRF-CRP17-2017-02

This research / project is supported by the National Medical Research Council - Young Individual Research Grant
Grant Reference no. : NMRC/OFYIRG/18MAY-0008
Description:
ISSN:
0027-8424
1091-6490
Files uploaded:

Files uploaded:

File Size Format Action
20220210-final-proof-from-press-pnas.pdf 781.12 KB PDF Open