Human telomerase is directly regulated by non-telomeric TRF2-G-quadruplex interaction

Area of Science:

• Molecular Biology
• Cancer Biology
• Epigenetics

Background:

• Human telomerase reverse transcriptase (hTERT) is suppressed in normal cells, leading to telomere erosion and senescence.
• hTERT reactivation maintains telomeres and drives over 90% of cancers, but its regulation is not fully understood.

Purpose of the Study:

• To investigate the direct causal link between telomeres and telomerase regulation.
• To elucidate the mechanism by which TRF2 influences hTERT expression.

Main Methods:

• Chromatin immunoprecipitation assays to assess TRF2 binding to the hTERT promoter.
• Analysis of H3K27 trimethylation levels at the hTERT promoter.
• Investigating the impact of hTERT promoter mutations on TRF2 binding and hTERT expression.
• Utilizing ligand-induced G-quadruplex stabilization to restore TRF2 binding and hTERT suppression.

Main Results:

• TRF2 binds to G-quadruplexes in the hTERT promoter and recruits EZH2/PRC2.
• This binding causes H3K27 trimethylation, repressing hTERT in both normal and cancer cells.
• Recurrent hTERT promoter mutations destabilize G-quadruplexes, impairing TRF2 binding in glioblastoma.
• Stabilizing G-quadruplexes restored TRF2 binding, H3K27 trimethylation, and hTERT re-suppression.

Conclusions:

• A novel mechanism linking telomere factor TRF2 to hTERT repression via epigenetic modification (H3K27 trimethylation) is uncovered.
• This pathway is crucial for maintaining hTERT suppression and is disrupted in cancer.
• Targeting this telomere-telomerase axis holds potential for cancer therapy, aging interventions, and regenerative medicine.