Telomerase RNA processing: Implications for human health and disease
Neha Nagpal, Suneet Agarwal
Abstract
Telomeres are composed of repetitive DNA sequences that are replenished by the enzyme telomerase to maintain the self-renewal capacity of stem cells. The RNA component of human telomerase (TERC) is the essential template for repeat addition by the telomerase reverse transcriptase (TERT), and also serves as a scaffold for several factors comprising the telomerase ribonucleoprotein (RNP). Unique features of TERC regulation and function have been informed not only through biochemical studies but also through human genetics. Disease-causing mutations impact TERC biogenesis at several levels including RNA transcription, post-transcriptional processing, folding, RNP assembly, and trafficking. Defects in TERC reduce telomerase activity and impair telomere maintenance, thereby causing a spectrum of degenerative diseases called telomere biology disorders (TBDs). Deciphering mechanisms of TERC dysregulation have led to a broader understanding of noncoding RNA biology, and more recently points to new therapeutic strategies for TBDs. In this review, we summarize over two decades of work revealing mechanisms of human telomerase RNA biogenesis, and how its disruption causes human diseases.