# Discovery and characterization of a novel telomerase alternative splicing isoform that protects lung cancer cells from chemotherapy induced cell death

## TL;DR

A new telomerase isoform, TERT Delta 2–4, was found to help lung cancer cells resist chemotherapy, suggesting it plays a key role in cancer survival.

## Contribution

Discovery of a novel TERT isoform, TERT Delta 2–4, and its role in chemotherapy resistance in lung cancer cells.

## Key findings

- TERT Delta 2–4 is overexpressed in induced pluripotent stem cells and cancer cells.
- Overexpression of TERT Delta 2–4 increases resistance to cisplatin-induced cell death.
- Knockdown of TERT Delta 2–4 reduces clonogenicity and resistance in cancer cells.

## Abstract

All cancer cells must adopt a telomere maintenance mechanism to achieve replicative immortality. Most human cancer cells utilize the enzyme telomerase to maintain telomeres. Alternative splicing of TERT regulates the amount and function of telomerase, however many alternative splicing isoforms of TERT have unknown functions. Single molecule long read RNA/cDNA sequencing of TERT revealed 45 TERT mRNA variants including 13 known and 32 novel variants. Among the variants, TERT Delta 2–4, which lacks exons 2–4 but retains the original open reading frame, was selected for further study. Induced pluripotent stem cells and cancer cells express higher levels of TERT Delta 2–4 compared to primary human bronchial epithelial cells. Overexpression of TERT Delta 2–4 enhanced clonogenicity and resistance to cisplatin-induced cell death. Knockdown of endogenous TERT Delta 2–4 in Calu-6 cells reduced clonogenicity and resistance to cisplatin. Our results suggest that TERT Delta 2–4 enhances cancer cells’ resistance to cell death. RNA sequencing following knockdown of Delta 2–4 TERT indicates that translation is downregulated and that mitochondrial related proteins are upregulated compared to controls. Overall, our data indicate that TERT produces many isoforms that influence the function of TERT and the abundance and activity of telomerase.