Plenary Paper HEMATOPOIESIS AND STEM CELLS Inherited bone marrow failure associated with germline mutation of ACD, the gene encoding telomere protein TPP1

Telomeres are the repetitive DNA–protein complexes at the ends of linear chromosomes, which shorten with every cell division in human somatic cells. Telomere shortening eventually leads to the activation of a DNA damage response and cellular senescence or apoptosis. Germ cells, stem cells, and cells in the developing human embryo overcome telomere shortening by expression of the ribonucleoprotein enzyme telomerase. Telomerase catalyzes addition of telomeric DNA repeats to chromosome ends by reverse transcription of a template sequence within its integral RNA subunit (hTR in humans). The core active human telomerase complex consists of hTR, the reverse-transcriptase protein subunit (hTERT), and the RNA-binding protein dyskerin. Telomerase interacts with many other proteins during its biogenesis and transport to the telomere, such as the protein TCAB1 (also known as WDR79 and WRAP53), which is responsible for trafficking telomerase to nuclear Cajal bodies and from there to the telomere. Individuals who inherit extremely short telomeres are at risk of developing one of a group of disorders collectively termed “short telomere syndromes.” The first of these diseases linked to short telomeres was dyskeratosis congenita (DC), defined by a mucocutaneous triad of abnormal skin pigmentation, oral leukoplakia, and nail dystrophy and characterized by progressive bonemarrow failure due to depletion of functional hematopoietic progenitor and stem cells. Patients with DC, or its more severe variants Revesz syndrome and Hoyeraal-Hreidarsson syndrome, harbor deleterious mutations in the genes encoding dyskerin, hTR, hTERT, TCAB1, the dyskerin-associated proteins Nop10 and Nhp2, or the telomere-binding proteins TIN2, CTC1, and RTel1. Patients with acquired or familial aplastic anemia, but lacking the other clinical features of DC, can also carry short telomeres and mutations in the genes encoding hTR or hTERT. The telomere-binding protein TPP1 (encoded by the gene adrenocortical dysplasia homolog [mouse] [ACD] and previously known as PTOP, PIP1, or TINT2) is critical for telomere stability and length regulation. TPP1 binds to the telomere via interaction with TIN2 and in turn tethers the single-stranded DNA binding protein Pot1 to telomeres. TPP1 is required for Pot1 to perform its role in protecting telomeres from being recognized as DNA damage. The Pot1/TPP1 heterodimer also has a separate role in promoting the processivity of telomerase, ie, its ability to synthesize long tracts of