Ayush Kumar
BIOL303H: Fundamentals of Genetics
Bert Ely
November 22nd, 2011
Relating Telomere Maintenance and Function in Diabetes and Melanoma
The area of repetitive DNA sequences at the end of a chromosome is known as a
telomere. Telomeres act as guardians of genetic information by protecting the ends of
chromosomes. Physically, telomeres are heterochromatic domains composed of repetitive DNA
(mostly TTAGGG repeats) bound to an array of specialized proteins (Donate and Blasco, 2011).
With each passing cell division, telomere ends decrease in length, before the enzyme telomerase
reintroduces short strands of repetitive DNA to repair the telomere. Telomerase is found in
embryonic stem cells, allowing them to divide repeatedly and with greater frequency.
For Type 2 diabetes, shortened telomeres lead to β-Cell mass reduction and failure, and
as this cell mass promotes insulin levels in the body, to the increasing incidence of diabetes with
age (Guo et al., 2011). When a telomere reaches a critically short level, it is recognized as DNA
damage and activates a p53-mediated DNA damage signaling response that impairs cell
mobilization and leads to a state of suboptimal tissue regeneration (Donate and Blasco, 2011).
Stem cells have a habit of expressing high levels of telomerase, since these cells must replicate
efficiently. To maintain organ systems, but high levels of telomerase increases the chances of a
cancer developing. In contrast, telomerase activity in adult tissues is not sufficient to prevent
telomere shortening associated with aging.
Image 1: Short telomeres over time and long telomeres through mutation and their effects
Type 2 diabetes is a metabolic disorder, designated by levels of high blood glucose and
an insulin deficiency. A certain kind of cell found in the pancreas, known as the β-cells, make
and release insulin and thus control the glucose level in the blood. In its earliest stages, type 2
diabetes is marked by an impaired glucose tolerance and defective insulin secretion, before the
aforementioned β-cells begin to deplete. Recent genomic studies have underscored the influence
of inherited factors, for example shorter telomeres, that affect β-cell integrity and function in age
related diabetes (Saxena et al., 2007). In addition, mutations in both TERT, which is the
telomerase reverse transcriptase, and in the telomerase RNA can cause telomere shortening,
which impairs organ function and causes stem cell loss. To study the impact of shortened
telomeres, Nini Guo's team at Johns Hopkins School of Medicine An approach done with mice
possessing shortened telomeres and impaired glucose tolerance (Guo et al., 2011).
Mice heterozygous null for telomerase RNA were compared to wild type mices. After
initial serum glucose and fasting insulin levels were measured, insulin release in response to a
glucose stimulus was measured, and mice with shorter telomeres had impaired insulin secretion.
The data indicates that short telomeres impair glucose tolerance through defective release of
insulin, and that this defect is independent of β-cell mass, size, and insulin content, showing that
the expected cause of impaired insulin secretion as a result of diabetes, the total β-cell mass, was
not a factor.
In Figure 1,Graphs A-D show the high body glucose and low insulin level present in mice with
shortened telomeres initially, which Graphs E-F show that after a glucose stimulus, insulin levels
in the experimental mice are much lower than the wild type control, showing the onset of
diabetic condition. The fact that the low insulin secretion occurred independent of any change to
the total mass of the β-cell suggests that shortened telomeres are a relevant modifier and signal of
diabetes risk (Guo et al., 2011).
About 15% of human cancer cells bypass their cell death and thus divide forever through
using a telomerase-independent length maintenance mechanism referred to as an Alternative
Lengthening of Telomeres, or ALT. ALT was discovered in budding yeast cells which bypassed
the expected senescence (cell death) and possessed long, telomeric repeats (Lundblad and
Blackburn, 1993). Through using extrachromosomal circular DNA also containing long
telomeric sequences, these survivor cells and human ALT cells amplify their own telomeric
DNA. To study ALT, Chang et al. (2011) analyzed survivor cells of yeast Saccharomyces
cerevisiae at their telomeric extension events, immediately after their emergence from a
senescent culture. The telomeres at these sites appeared longer and extended, an unexpected
difference from the shortened telomeres which triggered senescence in mouse and yeast studies.
From studies of prokaryotes, yeast, and mammalian cells, recombination efficiency is directly
proportional to the length of the substrate DNA. Therefore, Chang et al. (2011) proposed the idea
that once a cell survives expected senescence through DNA recombination, the longer telomeres
are better sites for recombination and will recombine first. Short telomeres get extended as well,
allowing the cell to continuously escape senescence.
Another related telomere and senescence study analyzed developing melanoma cells. Cell
I immortality is a characteristic of various cancers. Less clear is whether cancer cells early in
tumor formation are immortal, or if the cellular trait is gained as the cancer spreads and
strengthens. Cultured cancer cells, such as those of metastatic melanoma, appear immortal, while
uncultured cells in earlier stages show senescence markers (Soo et al., 2011). Thus, only four out
of 37 thin and thick melanoma cultures exhibited immortality (Table 1). All cultures in arrested
development displayed senescence markers such as β-galactosidase, nuclear p16, and
heterochromatic foci. However, even advanced melanoma cultures and uncultured vertical
growth-phase melanomas exhibited signs of telomericrisis, suggesting that immortalization and
telomere maintenance are selected late in tumor developments (Soo et al., 2011). A model for
tumor progression is shown in Figure 2.
Figure 2: Proposed update of melanoma progression (Soo et al.,2011)
In type 2 diabetes and cancerous cells, the activity and state of the telomeres
govern much of the cellular functions of the diseases. The established short telomere effect is
present in conjunction with human aging and a reduced level of β-cell signaling, foreshadowing
the effects and onset of diabetes by decreasing the amount of insulin able to be produced and
excreted. The interrelated phenomena of cell immortality to cancerous growth places telomeres
at a critical position in the effort to understand and combat various cancers, as the activity of the
telomere in elongation can both protect the body's cells from death, yet eventually lead to cancer
cells bypassing senescence via activating telomerase reverse transcriptase for unparalleled cell
and tumor growth (Chang et al., 2011). The 2009 Nobel Prize in Medicine went to Elizabeth
Blackburn, Carol Greider, and Jack Szostak "for the discovery of how chromosomes are
protected by telomeres and the enzyme telomerase", thus representing the significant strides
humans can make in understanding, and changing, life by examining telomeres.
Literature Cited
Chang, M., Dittmar, J.C., Rothstein, R. (2011). Long Telomeres are Preferentially Extended
During Recombination-Mediated Telomere Maintenance. Nature Structural & Molecular
Biology. 18(4); 451-456
Donate and Blasco. (2011). Telomeres in cancer and ageing. Philosophical Transactions of the
Royal Society B: Biological Sciences. 366, 76-84
Guo, et al. (2011). Short Telomeres Compromise Beta-Cell Signaling and Survival. Public
Library of Science: One. Vol 6, Issue 3
Saxena, et al. (2007). Genome-wide association analysis identifies loci for type 2 diabetes and
triglyceride levels. Science: 316(5829)
Soo, et al. (2011). Malignancy without immortality? Cellular immortalization as a possible late
event in melanoma progression. Pigment Cell Melanoma Research. 24; 490-503