Identify modulators of telomerase activity

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

This project focuses on dissecting telomerase regulation and identifying potential points of intervention in telomerase-positive cancers. Our primary focus this year was to build and apply a single-cell assay capable of distinguishing recruitment from function. Single-Cell Telomerase Assay Development: We developed a single-cell assay in mouse embryonic stem cells that quantitatively measures telomerase activity and allows dissection of upstream recruitment pathways. Using this system, we showed that TPP1 is essential for telomerase recruitment through its interaction with TIN2, whereas POT1 is not required for recruitment but is essential for end protection. These results argue against the classical open-versus-closed telomere state model and instead support a modular view of telomerase regulation. Application for Screening: This assay will be used to identify genetic and small-molecule modulators of telomerase recruitment or activity. This platform lays the foundation for discovering selective telomerase inhibitors that preserve telomere stability in normal cells. Publications Manuscript under review: "Modular separation of telomerase recruitment and end protection in stem cells". Core findings include the genetic separation of recruitment (TPP1-TIN2) from protection (POT1), providing mechanistic clarity and identifying potential druggable nodes. This work supports both Projects 1 and 3 but is central to the identification and targeting of telomerase modulators.