Telomere Transcripts Target Telomerase in Human Cancer Cells

Area of Science:

• Molecular Biology
• Cancer Research
• Genetics

Background:

• Long non-coding RNAs, telomeric repeat-containing RNA (TERRA), are known to regulate telomere maintenance mechanisms (TMMs).
• TERRA has been implicated in blocking telomerase activity (TA), a key TMM in many tumors.

Purpose of the Study:

• To investigate the effects of recombinant TERRA expression on TMMs and cell growth in tumor cell lines.
• To compare the impact of TERRA in telomerase-positive versus alternative lengthening of telomeres (ALT) cancer cells.

Main Methods:

• Established adeno- and lentivirus constructs for expressing recombinant TERRA in six human tumor cell lines.
• Analyzed telomerase activity, TERRA expression levels, cell viability, population doubling time, telomere length (TL), and clonal growth post-infection.
• Utilized dominant-negative or shRNA constructs targeting hTERT as controls.

Main Results:

• TERRA expression in telomerase-positive cells increased TERRA levels 1.3-2.6 fold, decreasing TA by 25%-58%.
• Ectopic TERRA expression did not impact population doubling time, cell viability, or TL.
• Clonal growth was reduced in TA cells but unaffected in ALT cells; ALT cells were generally unresponsive to treatments.

Conclusions:

• TERRA can inhibit telomerase activity and reduce clonal growth in a telomere maintenance mechanism-dependent manner.
• Established viral expression systems provide tools to study TERRA's role in cellular processes.
• TERRA represents a potential therapeutic target for telomerase-dependent cancers.