Telomere

Telomere

What is a telomere?

Telomeres are distinctive structures (sections of DNA) found at the ends of linear chromosomes. They consist of the same short DNA sequence repeated over and over again.

Telomeric sequences are non coding sequences.

Figure 1

Structure of telomere

Each telomere consists of a long series of tandemly repeated hexanucleotide sequences. There may be 100-1000 repeats, depending on the organism.

  • In Tetrahymena (protozoan), telomeric sequence is only 12 to 16 nucleotides long.
  • In lower vertebrates, it may be several hundred nucleotides long.
  • In higher eukaryotes (including mammals) telomeres are thousands of base pairs long.
  • In humans the telomere sequence is TTAGGG. The complementary DNA strand is AATCCC
  • This sequence of TTAGGG is repeated approximately 2,500 times in humans.
  • Certain bacteria possess telomeres in their linear genetic material which are of two types;

Hairpin telomere: As its name implies, the telomeres bend around from the end of one DNA strand to the end of the complimentary strand.

Invertron telomere: This type acts to allow an overlap between the ends of the complimentary DNA strands.

All telomeric sequences can be written in the general form:

Cn(A/T)m   Where n ˃ 1 , m = 1 – 4

Table 1: Telomeric sequences in eukaryotes (G-rich strand of the double helix)

Most of the telomeric DNA is double stranded: One of the strands is called G – rich strand and the other one is called C – rich strand.

G-rich single strand forms a terminal 3′ overhang. (It extends beyond C rich strand in several nucleotides)

What are the major functions of telomeres?

1) They protect the ends of our chromosomes by forming a cap (like the plastic tips at the end of shoelaces protecting them) and confer stability to linear DNA molecule by preventing their degradation by nucleases.

2) They help to organize each of our 46 chromosomes in the nucleus of our cells.

3) They function to protect the ends of chromosomes from sticking to each other and from DNA repair mechanism.

  • If the telomeres were not there, our chromosomes may end up sticking to other chromosomes.

4) They allow the chromosome to be replicated properly during cell division. (Telomere ensures that the cells will not lose any important genetic information during cell division

  • Every time a cell carries out DNA replication, the chromosomes are shortened by about 25-200 bases (A, C, G, or T) per replication.
  • However, because the ends are protected by telomeres, the only part of the chromosome that is lost is the telomere, and the DNA is left undamaged.
  • Without telomeres, important DNA would be lost every time a cell divides (usually about 50 to 70 times).
  • This would eventually lead to the loss of entire genes.

Different organisms use any of three different methods known to protect the ends of the chromosomes.

1) The guanine-rich DNA can form complex structure known as G-quadruplexes. (Figure 3)

  • Guanine bases have an unusual capacity to associate with one another.
  • The single-stranded G-rich tail of the telomere can form “quartets” of G residues.
  • Each quartet contains 4 guanines that hydrogen bond with one another to form a planar structure. Each guanine comes from the corresponding position in a successive TTAGGG repeating unit.
  • A series of quartets are stacked in a helical manner.

2) Binding of proteins to 3’ end of telomere

Example: In the ciliate Oxytricha nova, a protein called the telomere end-binding protein (TEBP) attaches to the 3’ ends of telomeres and protects them.

3) t-loop formation at the end of mammalian telomeres.

Telomeres form little loops at the end of the chromosomes, which are called the t-loops

Figure 3: Structure of t loop

How they are formed?

  • The single stranded 3’ end of the telomere (3’ overhang) is folded back and paired with its complement in the double-stranded portion of the telomeric DNA upstream.
  • Thus very short telomeres (in old aging cells or sometimes cancer cells) can no longer form t-loops.
  • The exposure of these chromosome ends, 3’ overhangs which cannot be inserted back into the DNA of the chromosome, would alert the cells and thus stop cells from dividing.

Proteins involved in t – loop formation

Telomeric repeat-binding factor 1: TRF1

Telomeric repeat-binding factor 2: TRF2

  • TRF1 and TRF2 appear to help telomeric DNA in mammalian cells form a t loop
  • TRF1 help to bend the DNA into shape for strand invasion.
  • TRF2 binds at the point of strand invasion and may stabilize the displacement loop.
  • They have a role in telomere stabilization and telomere-length regulation.
Figure 4: Mechanism of t loop formation

What happens to telomere as we age?

  • Each time a cell divides, 25-200 bases are lost from the ends of the telomeres on each chromosome.
  • Two main factors contribute to telomere shortening during cell division:

1) The “end replication problem” during DNA replication: Accounts for the loss of about 20 base pairs per cell division.

2) Oxidative stress: Accounts for the loss of between 50-100 base pairs per cell division. The amount of oxidative stress in the body is thought to be affected by lifestyle factors such as diet, smoking and stress.

  • When the telomere becomes too short, the chromosome reaches a ‘critical length’ and can no longer be replicated.
  • This ’critical length’ triggers the cell to die by a process called apoptosis, also known as programmed cell death.
Figure 5: telomere shortening during cell division

How is telomere length maintained?

  • Telomerase is an enzyme that adds the TTAGGG telomere sequence to the ends of chromosomes.
  • Telomerase is only found in very low concentrations in our somatic cells (these cells do not regularly use telomerase). They age leading to a reduction in normal function. The result of ageing cells is an ageing body.
  • Telomerase is found in high levels in germline cells (egg and sperm) and stem cells. In these cells telomere length is maintained after DNA replication and the cells do not show signs of ageing.
  • Telomerase is also found in high levels in cancer cells. This enables cancer cells to be immortal and continue replicating themselves. If telomerase activity was switched off in cancer cells, their telomeres would shorten until they reached a ‘critical length’. This would, prevent the cancer cells from dividing uncontrollably to form tumors.
  • The action of telomerase allows cells to keep multiplying and avoid ageing.

An inherited disease called the Werner’s syndrome that causes patients to age much more rapidly than normal, is characterized by abnormal telomere maintenance

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