Molecular mechanisms of telomere biology disorders

Abstract

Genetic mutations that affect telomerase function or telomere maintenance result in a variety of diseases collectively called telomeropathies. This wide spectrum of disorders, which include dyskeratosis congenita, pulmonary fibrosis, and aplastic anemia, is characterized by severely short telomeres, often resulting in hematopoietic stem cell failure in the most severe cases. Recent work has focused on understanding the molecular basis of these diseases. Mutations in the catalytic TERT and TR subunits of telomerase compromise activity, while others, such as those found in the telomeric protein TPP1, reduce the recruitment of telomerase to the telomere. Mutant telomerase-associated proteins TCAB1 and dyskerin and the telomerase RNA maturation component poly(A)-specific ribonuclease affect the maturation and stability of telomerase. In contrast, disease-associated mutations in either CTC1 or RTEL1 are more broadly associated with telomere replication defects. Yet even with the recent surge in studies decoding the mechanisms underlying these diseases, a significant proportion of dyskeratosis congenita mutations remain uncharacterized or poorly understood. Here we review the current understanding of the molecular basis of telomeropathies and highlight experimental data that illustrate how genetic mutations drive telomere shortening and dysfunction in these patients. This review connects insights from both clinical and molecular studies to create a comprehensive view of the underlying mechanisms that drive these diseases. Through this, we emphasize recent advances in therapeutics and pinpoint disease-associated variants that remain poorly defined in their mechanism of action. Finally, we suggest future avenues of research that will deepen our understanding of telomere biology and telomere-related disease.

Keywords: dyskeratosis congenita; telomerase; telomerase assembly; telomerase recruitment; telomere; telomere shortening; telomeropathies.

Figure 1

Model for telomerase biogenesis and telomere maintenance. TBD-associated proteins and RNA (TR) are labeled in red. TCAB1 (multicolored) is shown in the cytosol bound to TRiC (gray) before localizing to Cajal bodies. TR (black) is processed by PAPD5 and PARN (navy blue) before localizing in Cajal bodies. The telomerase holoenzyme (TERT [purple], TR, dyskerin [green], NHP2 [pink], NOP10 [lightorange], GAR1 [gray], and TCAB1) is assembled in Cajal bodies before being recruited to telomeres by the shelterin protein TPP1 (orange). For simplicity, the telomerase holoenzyme is shown with only one copy of NOP10, NHP2, or GAR1. TIN2 (yellow) is bound to shelterin proteins TPP1, TRF1, and TRF2. The CST complex (CTC1, STN1, TEN1; mauve) is depicted at newly synthesized ss telomeric DNA and RTEL1 (forest green) is shown unwinding DNA at a replication fork.

Figure 2

Domain organization of TERT, TPP1, TIN2, TCAB1, PARN, and RTEL1. Selected DC and HH mutations are shown in red, AA mutations are shown in orange, and PF mutations are shown in yellow. Amino acid numbering above the schematics indicates domain boundaries. Shading connecting domains of one protein to another represents protein–protein interactions mediated through the specified domains. The following proteins are described: TERT (Telomerase essential N-terminal domain [TEN], insertion in fingers domain [IFD; purple]). TPP1 (TIN2-binding motif of TPP1 [TBM], N-terminus of the OB [NOB; lavender], TEL patch residues are shown in cyan). TIN2 (TRF1 binding motif [FxLxP; navy blue], DC hotspot represents a cluster of DC mutations in TIN2). Dyskerin (pseudouridine synthase catalytic domain [TruB], RNA-binding domain [PUA]). TCAB1 (each of six WD repeats is indicated in the WD40-repeat domain). PARN (R3H domain [blue] splits the CAF1 nuclease domain [aqua]). RTEL1 (DEAH box [blue], PCNA binding box [PIP box-green], metal-coordinating C4C4 motif thought to bind TRF2 [C4C4 motif]).

Figure 3

Domain organization and interactions of TR. A schematic of TR secondary structure divided into domains (demarcated by boxes) containing key features (CAB box and template) highlighted in red. Arrows point to the regions of TR that indicated telomerase RNP proteins bind to.