Fig. 6: An updated model of human telomere length regulation.
From: Metabolic constraint of human telomere length by nucleotide salvage efficiency
To date, most data indicate that human telomere length is regulated by (1) the abundance of telomerase holoenzyme and (2) its interplay with telomere binding proteins. Based on the current findings and emerging human genetic data, we propose a revised model encompassing a third critical dimension of telomere length regulation in human cells: control of dNTP substrate levels available for telomere 5’-GGTTAG-3’ repeat synthesis by telomerase. dNTP substrate accumulation is limited by salvage efficiency including (a) deoxyguanosine (dG) metabolism by DCK, and (b) thymidine (dT) conversion to dTTP via TK125. dTTP can enhance dGTP production by allosteric binding to ribonucleotide reductase (RNR). Overcoming salvage constraints through dG or dT supplementation or by augmenting kinase activity robustly increases telomerase activity and telomere length. Conversely, guanine nucleoside metabolism via PNP and HGPRT to form guanosine ribonucleotides decreases telomere length, potentially by inhibiting RNR and depletion of dNTPs. Mutations that impair dTTP de novo synthesis lead to reduced telomerase substrate levels and impaired telomerase activity, as observed in patients with TYMS locus mutations who develop dyskeratosis congenita23. The dNTPase SAMHD1 prevents the accumulation of telomerase dNTP substrates and restricts telomerase activity. Our model provides a mechanistic framework for the recent association between genetic variation in dNTP metabolism genes and telomere length in states of health and disease.
