Elsevier

Seminars in Hematology

Volume 50, Issue 2, April 2013, Pages 165-174
Seminars in Hematology

Telomere Dynamics in Mice and Humans

https://doi.org/10.1053/j.seminhematol.2013.03.030Get rights and content

Telomeres are ribonucleoprotein structures capping the end of every linear chromosome. In all vertebrates, they are composed of TTAGGG repeats coated with specific protecting proteins. Telomeres shorten with each mitotic cell division, but telomerase, a reverse transcriptase, elongate telomeres in very specific cells, such as embryonic and adult stem cells. Although telomere sequence is identical in mice and humans and telomeres serve the same role of protecting chromosomes and genetic information from damage and erosion in both species, abnormalities in telomere maintenance and in telomerase function do not coincide in phenotype in humans and mice. The telomeres of most laboratory mice are 5 to 10 times longer than in humans, but their lifespan is 30 times shorter. Complete absence of telomerase has little expression in phenotype over several generations in mice, whereas heterozygosity for telomerase mutations in humans is sufficient to result in organ regeneration defect and cancer development. Patients with telomerase deficiency and very short telomeres may develop aplastic anemia, pulmonary fibrosis, or cirrhosis, whereas telomerase-null murine models display only modest hematopoietic deficiency and develop emphysema when exposed to cigarette smoke. In summary, telomerase deficiency in both humans and mice accelerate telomere shortening, but its consequences in the different organs and in the organism diverge, mainly due to telomere length differences.

Section snippets

Telomeres, Aging, and Longevity

As telomeres erode with cell division, serving as a “mitotic clock” for the proliferative history of a cell or tissue and resulting in cell senescence and apoptosis, telomere biology has been postulated as the molecular mechanism for physiologic and pathologic aging.10

In mice, specific serum proteins (CRAMP, stathmin, EF-1α, and chitinase) are elevated in late generation telomerase “knockout” mice.11 However, these changes only occur in aging mice, which are telomerase-deficient for several

Telomeres and Disease

In humans, defects in telomerase function result in progressive telomere shortening, which clinically manifests as severe diseases that are often fatal. X-linked dyskeratosis congenita is the prototypical human telomere disease; it is characterized by mucocutaneous dystrophy in boys associated with aplastic anemia, the most common cause of death, usually in the first decade of life.35 Patients with dyskeratosis congenita commonly have other organs affected, mainly the lungs (pulmonary fibrosis),

Telomeres and Cancer

Almost 100 years ago, Boveri postulated chromosomal instability as the initiating pathogenic event in oncogenesis.60 Consistent with this hypothesis, most cancers have an aneuploid genome, as well as qualitative chromosome changes, as deletions or translocations. Telomere attrition has been proposed as a mechanism for the loss or gain of chromosomes. In the absence or decrease of telomerase activity, mutation rates increase as a result of terminal chromosome deletions and repeated cycles of

Conclusions

In mammals, telomere length inversely correlates with life span, whereas telomerase expression inversely correlates with body mass; short-lived species with small body mass, such as mice, evolved to have much longer telomeres and express telomerase at the expense of abandoning a role of telomeres in replicative aging, as observed in humans. Thus, murine telomerase knockout models have been useful in identifying and characterizing the major basic biology of telomeres and telomerase, but in depth

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    Conflicts of interest: none.

    Supported in part by FAPESP (R.T.C.) and the NIH Intramural Research Program (B.D.).

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