Fueling for the finish line: Control of human telomerase activity by nucleotide metabolism

Telomeres are repetitive DNA sequences that preserve genome integrity. Human telomere length is kept in a tight window through a balance between telomere erosion during genome replication and telomere elongation by the telomerase reverse transcriptase. In humans, genetically determined telomere length is associated with lifespan, while inherited defects in telomere length maintenance genes predispose to a spectrum of lethal diseases termed telomere biology disorders (TBDs). Recently, dNTP metabolism has emerged as a previously underappreciated pathway that is critical for human telomerase regulation and telomere length control. Genome-wide association studies have implicated variation in several dNTP metabolism genes with human telomere length. Genetic variants at the TYMS locus, which encodes the rate limiting thymidine synthesis enzyme thymidylate synthase, have been shown to cause the TBD dyskeratosis congenita. Genome-wide CRISPR/Cas9 functional screening has linked telomere length control to multiple key dNTP metabolism genes. Remarkably, mechanistic studies emerging from these genetic data have revealed a profound, bidirectional sensitivity of human telomerase activity to cellular dNTP levels, that is readily manipulated through several metabolic control nodes. Here, we review the emerging genetic evidence and mechanistic studies supporting the relationship between dNTP metabolism and telomere length control. We present an integrated model for human telomerase regulation, wherein the levels of dNTP substrates govern telomerase reverse transcriptase activity and in turn human telomere length. We discuss the therapeutic prospects and recent trials for manipulating dNTP metabolism to treat TBDs and related degenerative diseases.