Telomeres are comprised of repetitive sequences at the ends of chromosomes that promote genome stability [1], [2]. Telomeres shorten during cell division due to the inability of DNA replication machinery to fully copy chromosome ends [3], [4]. When telomeres reach a critically short length, they trigger cellular senescence, preventing further cell division [5]. Telomere length thus limits cellular replicative capacity. This limit is overcome by expression of telomerase, a holoenzyme complex that uses an integral RNA template and reverse transcriptase to synthesize new telomere repeats from dNTP substrates [6], [7]. Telomerase activity is highly constrained by the availability of its core enzymatic components: the reverse transcriptase TERT and the non-coding RNA template TERC. Expression of TERT is restricted to stem cells, the germline, and other regenerative cells [8]. TERT expression can be considered an on-off switch for cellular telomerase activity. In cells that express TERT, the abundance of functional telomerase is highly sensitive to levels of TERC [9], which itself is under tight regulation at the levels of transcription, post-transcriptional end processing, dyskerin H/ACA ribonucleoprotein assembly, and subcellular localization to Cajal bodies [10]. Telomere repeat synthesis is also regulated by the shelterin and CST1/STN1/TEN1 (CST) complexes, which govern the ability of telomerase to access the telomere 3’ end [11], [12]. To date, studies of human telomerase regulation have focused on the abundance of the telomerase holoenzyme and its interplay with one of its substrates, the chromosome end (Fig. 1). The other substrates, deoxyribonucleotides triphosphates (dNTPs), have largely been assumed to be in excess for telomere synthesis given their ∼5-log higher utilization for genome replication.

Telomere length maintenance is critical for human health, and perturbations of telomerase function cause disease. Genetically determined telomere length is associated with lifespan and common pathologies in the general population [13]. Inherited mutations in telomerase and telomere maintenance genes that result in premature telomere shortening predispose to a spectrum of severe degenerative diseases collectively referred to as telomere biology disorders (TBDs) [14]. Genetic discoveries in the TBDs over the past 25 years have reaffirmed and expanded the prevailing models of telomere length control, identifying several factors and new mechanisms underlying human telomerase accumulation and recruitment to the telomere end. Unexpectedly, several independent lines of human genetic and functional evidence now indicate that telomerase is highly sensitive to cellular dNTP levels [15], [16], [17], [18], [19]. dNTP levels are tightly controlled by a balance between de novo synthesis from ribonucleotides, salvage from nucleosides, consumption for DNA synthesis and repair, and catabolism (Fig. 2). Here, we review recent advances in our understanding of how dNTP metabolism contributes to human telomere length regulation. We present a model for telomere length control wherein perturbations in the levels of dNTP substrates available for telomere synthesis by telomerase play as important a role as telomerase abundance or recruitment to chromosome ends (Fig. 1). We discuss the clinical and evolutionary implications of this model, focusing on telomere length control in human cells. We will not engage studies in yeast [20], [21], [22], [23], which have been discussed elsewhere [20].