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Review
. 2010;56(4):390-403.
doi: 10.1159/000268620. Epub 2009 Dec 17.

Telomeres and immunological diseases of aging

Nicolas P Andrews  1 , Hiroshi Fujii, Jörg J Goronzy, Cornelia M Weyand
Affiliations
Review

Telomeres and immunological diseases of aging

Nicolas P Andrews et al. Gerontology. 2010.

Abstract

A defining feature of the eukaryotic genome is the presence of linear chromosomes. This arrangement, however, poses several challenges with regard to chromosomal replication and maintenance. To prevent the loss of coding sequences and to suppress gross chromosomal rearrangements, linear chromosomes are capped by repetitive nucleoprotein structures, called telomeres. Each cell division results in a progressive shortening of telomeres that, below a certain threshold, promotes genome instability, senescence, and apoptosis. Telomeric erosion, maintenance, and repair take center stage in determining cell fate. Cells of the immune system are under enormous proliferative demand, stressing telomeric intactness. Lymphocytes are capable of upregulating telomerase, an enzyme that can elongate telomeric sequences and, thus, prolong cellular lifespan. Therefore, telomere dynamics are critical in preserving immune function and have become a focus for studies of immunosenescence and autoimmunity. In this review, we describe the role of telomeric nucleoproteins in shaping telomere architecture and in suppressing DNA damage responses. We summarize new insights into the regulation of telomerase activity, hereditary disorders associated with telomere dysfunction, the role of telomere loss in immune aging, and the impact of telomere dysfunction in chronic inflammatory disease.

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Figures

Fig. 1
Fig. 1
Organization of telomere ends by the shelterin complex. a Schematic of the shelterin complex. The duplex-specific shelterin proteins TRF1 and TRF2 and the single-strand-binding protein POT1 directly recognize telomere sequences via oligonucleotide- or oligosaccharide-binding domains. TPP1 is essential for the recruitment of POT1 to telomeres. TIN2 forms a bridge between these components and is crucial for shelterin stability. Mammalian Rap1, whose function is still unclear, requires TRF2 for telomere localization as it lacks a DNA binding domain. Both TRF2 and TRF1 exhibit in vitro DNA remodeling activity and are thought to promote the formation of telomeric T and D loops in vivo (as in b). TRF2 and POT1 have a critical role in suppressing the DNA damage proteins ATM and ATR, respectively. POT1 binds the entire length of the 3'-overhang (not shown here) [4]. b Telomeric DNA is organized into T and D loops. The topological arrangement of telomeric ends into T and D loops by shelterin components is thought to prevent the initiation of DNA damage responses at telomeres and to regulate telomere elongation via inhibition of telomerase access to the 3'-overhang.
Fig. 2
Fig. 2
Schematic of the hTERT promoter. The hTERT gene is located on the short arm of chromosome 5 at 5p15.33. The binding sites of transcriptional activators and repressors are indicated [148]. The starred transcription factors are known to affect hTERT transcription in lymphocytes.
Fig. 3
Fig. 3
The multiple pathways affecting telomeric length. Telomere homeostasis is determined by the balance between telomeric repair and factors that promote erosion of telomeric sequences.
See this image and copyright information in PMC

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