ZBED6CL: a novel interactor in the telomerase regulatory network

Abstract

Telomeres are nucleoprotein structures that protect the ends of linear chromosomes. In somatic cells, telomeric DNA shortens with each round of division, leading to replicative senescence. Senescence can be overcome by the activation of telomerase, an enzyme that maintains telomere lengths through the synthesis of telomeric repeats. Though typically suppressed, the catalytic component (hTERT) becomes reactivated in the majority of cancers to counteract telomere shortening and achieve proliferative immortality. While activation of telomerase is critical for tumorigenesis, the underlying mechanisms of activation and regulation remain to be fully elucidated. Here, we use human cancer and stem cells to investigate the role of the uncharacterised protein ZBED6CL in telomerase regulation and telomere maintenance.

We demonstrate that knockdown of ZBED6CL in multiple cancer cell lines induces an increase in assembled telomerase, indicative of ZBED6CL acting as a regulator of telomerase homeostasis. We further determine that ZBED6CL acts downstream of transcription to repress levels of assembled telomerase such that, upon ZBED6CL depletion, telomerase activity is enhanced, resulting in increased localisation to telomeric ends, culminating in substantial telomere lengthening. Proteomic data reveal the TCP-1 Ring Complex (TRiC) chaperonin as the primary interactor of ZBED6CL, and we further identify a ZBED6CL–TRiC–hTERT axis with a hypothesised role for ZBED6CL as a co-chaperone regulating hTERT folding by TRiC.

Overall, our data identify ZBED6CL as a novel regulator of hTERT maturation in telomerase-positive cells. Our data support a mechanism of hTERT folding by TRiC regulated by ZBED6CL. Characterisation of ZBED6CL as a novel regulator of telomerase will further our understanding of telomere maintenance and cellular immortalisation to inform the development of novel, mechanism-based therapeutics with relevance to the cancer, ageing, and regenerative medicine fields.