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Review
. 2014 May 12;205(3):289-99.
doi: 10.1083/jcb.201401012.

Cell biology of disease: Telomeropathies: an emerging spectrum disorder

Brody Holohan  1 , Woodring E Wright, Jerry W Shay
Affiliations
Review

Cell biology of disease: Telomeropathies: an emerging spectrum disorder

Brody Holohan et al. J Cell Biol. .

Abstract

A constellation of related genetic diseases are caused by defects in the telomere maintenance machinery. These disorders, often referred to as telomeropathies, share symptoms and molecular mechanisms, and mounting evidence indicates they are points along a spectrum of disease. Several new causes of these disorders have been recently discovered, and a number of related syndromes may be unrecognized telomeropathies. Progress in the clinical understanding of telomeropathies has in turn driven progress in the basic science of telomere biology. In addition, the pattern of genetic anticipation in some telomeropathies generates thought-provoking questions about the way telomere length impacts the course of these diseases.

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Figures

Figure 1.
Figure 1.
Molecular biology of telomeropathies. The processes required to correctly replicate and extend telomeres are outlined; genes with known disease-causing mutations are denoted in red. Telomeres are packaged in a “T-loop” configuration characterized by G-strand invasion of the centromere-proximal double-stranded DNA. The T-loop must be dissociated before replication of the telomere can take place, which is accomplished by the RTEL1 helicase. DNA replication after T-loop resolution yields blunt-ended (from leading-strand synthesis) and RNA primer–ended (from lagging strand synthesis) telomere ends, which must be processed by the CST complex (composed of CTC1, STN1, and TEN1) and Apollo before telomerase activity. Telomerase is a complex containing TERT, TERC, and a dimer of the Dyskerin complex (Dyskerin, NOP10, NHP2, GAR1), and its assembly is promoted by TCAB1 in the Cajal body. After assembly, telomerase is localized to the replicated and processed telomere by TCAB1 and TPP1, where it can add 50–100 base pairs of new telomere repeats to the G-overhang. After telomerase activity, the CST complex and DNA polymerase-α perform a fill-in reaction and nucleolytic processing that yields an extended telomere closed to further action by telomerase.
Figure 2.
Figure 2.
Three models for the genetic anticipation observed in telomeropathies. Models that explain the anticipation observed in impaired telomere maintenance rely on different assumptions about the behavior of organ-specific stem cells. (A) If lung tissue stem cells have a constant cell division rate that is slower than hematopoietic stem cells during expansion of the multipotent progenitor (MPP) cell compartment but slower than the maintenance HSC division rate after the MPP pool is established, a point will exist in middle age when lung telomere lengths are shorter than MPP/HSC telomere lengths; if the patient started with an initial telomere length sufficient to avoid critically short telomeres until after this point, the patient will experience IPF, whereas patients with initial telomere lengths short enough that they encounter the critical length before that point will experience bone marrow failure. (B) If stem telomere attrition rates are synchronized after development, lung tissue must be subject to an alternative pathological threshold for telomere length that may be age dependent. In this case, patients with longer initial telomere lengths will never encounter critically short telomeres in their bone marrow, while their lung tissue will encounter the alternative threshold, leading to IPF. Patients with shorter initial telomere lengths will encounter critically short telomeres in their bone marrow before the critical threshold for the lungs, leading to bone marrow failure. (C) If telomere attrition rates are synchronous under normal conditions but lung tissue is differentially sensitive to environmental insults, an alternative pathological threshold is not necessary to explain the anticipation. Patients with longer initial telomeres will eventually be driven into IPF by environmental insults while never encountering the critically short telomere length in the HSC compartment, whereas patients with shorter initial telomere length will encounter the critical threshold before insult-driven lung failure. This model is further supported by observations of pulmonary fibrosis after pulmonary toxicity from bone marrow transplant conditioning.
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