Telomere 3’ overhang and disease

In this issue of Leukemia and Lymphoma, Yan et al. [1] report their finding of a small subset of Chinese patients with acute myeloid leukemia (AML) with telomerase reverse transcriptase (TERT) missense mutations. The presence of these mutations correlates with short telomeric 3’ overhang length and poor prognosis.

Telomeres are the special structures of the ends of chromosomes, which are characterized by G-rich tandem hexamers (5’-TTAGGG-3’) with an average length of 5–15 kb in humans. Telomeres are DNA-protein structures that can protect chromosome ends from degradation and fusion and are therefore crucial for the maintenance of genomic integrity. During DNA replication in each cell division, telomeres will gradually shorten at a rate of 50–200 bp because of the “end-replication problem.” The telomeres terminate in a 3’ single-stranded overhang of about 12–300 bp, called telomere 3’ overhang of the G-rich strand, which can be extended by telomerase in early S phase of the cell cycle, followed by fill-in of the C strand in late S phase. The telomere overhang folds back into the D-loop of the duplex telomere DNA to form a protective “T-loop,” which can prevent telomeres from degradation by exonucleases or from being recognized as damaged DNA [2]. Unlike telomere length, the overall 3’ overhang length does not significantly change with age. In addition, the shelterin complex of six telomere binding proteins binds to the telomere ends to help form the T-loop structure and maintain the telomere function. Disruption of the shelterin complex, by knock-out of TRF1, TRF2 or Pot1, results in the exposure and degradation of the 3’ overhang and the induction of a p53-dependent DNA damage response and chromosome fusion. Evidence indicates that telomere function is governed not only simply by telomere length, but also by an equilibrium between a “capped” and “uncapped” status of telomere ends that can trigger cell cycle arrest and DNA damage responses [3]. Although the mechanisms regulating telomere length have been relatively well studied, the regulation of 3’ overhang length, and the consequences of its dysregulation, are poorly understood.

Telomere maintenance is particularly important in proliferative tissues, and a variety of abnormalities including aplastic anemia and pulmonary fibrosis are found in patients with defective telomere maintenance due to mutations in gene products involved in telomerase, its biogenesis, or telomere structure [4]. Such patients usually have very short telomeres at the time of presentation. In a family with one such telomere syndrome, Hoyeraal–Hreidarsson syndrome, Lamm et al. [5] showed that although the telomerase expression and activity were normal, the telomeric 3’ overhangs were diminished in both blood cells and fibroblasts, suggesting that the primary defect in these patients lies in the telomere structure, rather than length. Calado et al. [6] also reported that disrupted telomere structure caused by shortened 3’ telomere overhangs may contribute to the mechanisms of abnormal hematopoietic compartment senescence and chromosomal instability in patients with aplastic anemia carrying telomerase complex mutations.

Telomeres are also important in cancer. Telomerase, which is not present in most somatic cells, is usually turned on in cancer cells to counteract the shortening telomeres due to high rates of proliferation. Lee et al. [7] reported that 3’ overhang length in human cells is widely distributed, and that normal cells exhibit relatively longer 3’ overhang length than that seen in cancer cells, suggesting that erosion of 3’ overhang length induces impaired telomere integrity and genomic instability. Interestingly, Hashimoto et al. [8] found that the most aggressive subtypes of endometrial cancers showed significantly longer 3’ overhangs (though still shorter than in healthy cells) than those with non-aggressive subtypes, suggesting that cancer cells with long 3’ overhang length have a growth advantage due to their stabilized telomere ends. Similarly, Kojima et al. [9] showed that in human colorectal cancer, long 3’ overhang is a poor prognostic factor. Taken together, these data suggest that, in addition to telomerase activity and telomere length, the length of 3’ overhang may also contribute to the development of cancers and may be a potential biomarker in determining the prognosis of patients. These results seem contradictory to those of Yan et al. [1], and it could be that cancers arising in patients with telomerase mutations are exceptional. In any case, more studies involving large numbers of patients are needed before solid conclusions are reached. However, the importance of telomere structure, including that of the 3’ overhang, may be important in both telomere syndromes and in cancer, and will likely be a fertile area for investigations in the near future.

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