Annual Report 2023

Division of Cancer Stem Cell

Kenkichi Masutomi, Mitsuhiro Machitani, Ken-Ichi Fujita, Mami Yasukawa, Saori Ueki

Introduction

 Research in the Division of Cancer Stem Cell is focused on deciphering the mechanisms that establish and maintain cancer stem cells and on developing novel therapeutic approaches for treating them. Specifically, our division studies the molecular links among a) telomerase and RNA-dependent RNA polymerase (RdRP) and b) RdRP and anticancer drugs.

Research Activities

1. Telomerase and RNA-dependent RNA polymerase

 Telomerase is a ribonucleoprotein complex that elongates telomeres. Human telomerase reverse transcriptase (TERT) functions as the catalytic subunit of telomerase and synthesizes telomere DNA repeats. Although the major function of TERT is believed to be telomere elongation, emerging evidence indicates that TERT exhibits various functions beyond telomere maintenance. We have reported that TERT has RdRP activity and synthesizes double-stranded RNAs. Our previous studies have indicated that post-transcriptional phosphorylation of TERT enhances RdRP activity in TERT without affecting telomerase activity and that TERT RdRP negatively regulates the expression of tumor suppressor genes, eventually leading to cancer progression. In addition, we have found a functional role of RdRP reaction by hTERT in R-loop regulation and maintenance of genome stability. We have revealed that hTERT associates with telomeric repeat-containing RNAs (TERRAs), transcribed from subtelomeric regions and dissolves R-loop structures. In addition, genome-scale CRISPR screening demonstrated that disruption of the Fanconi anemia/BRCA pathway and RdRP causes synthetic lethality through accumulation of R-loop structures, indicating that RdRP activity of hTERT functions to guard against genome instability through removal of R-loop structures (Nat Cell Biol. In press).

2.  RdRP and anticancer drugs

 We have confirmed a positive correlation between TERT protein expression levels and RdRP activity in various human cancer cell lines, indicating that RdRP inhibitors can be effective against various tumor types with high TERT expression levels. We continue to discover and characterize novel inhibitors of TERT-RdRP activity as potential anticancer drugs.

Future Prospects

 We aim to contribute to the development of new therapeutic methods targeting cancer stem cells by advancing biochemical and molecular biological studies on the new functions of TERT, which were originally found through our research activities.