DNA Telomeres

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Telomeres

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DNA Telomeres

Introduction

DNA telomeres are short, repeated sequences found at both ends of chromosomes. Telomeres and the action of telomerase, the enzyme that synthesizes them, help in completing replication of the lagging DNA strand. The presence of telomeres helps prevent the loss of DNA. Telomeres cap the chromosome ends and protect them from degradation and fusion. Telomerase is absent in somatic cells, so in time, the length of telomeres decreases, causing cell aging and cell-death.

What are Telomeres?

Telomeres are structures found at both ends of a chromosome, and are made of a single strand of DNA, that do not code for any gene. This DNA segment is made of a single sequence of nucleotides that is repeated many times. In vertebrates, the sequence is the guanine rich TTAGGG, where T and A stands for thymine and adenine respectively. In humans, it is repeated up to 3,000 times at birth.

telomereTelomeres are present at the end of linear DNA in all eukaryotes. Since the DNA in prokaryotes is a closed loop without open ends, telomeres are not found in them. However, some genera that do have linear DNA molecules have telomeres, like Streptomyces, Agrobacterium, and Borrelia.

 

 

Functions of Telomeres

  1. End replication problem

The DNA is a double stranded helix made of nucleotides, which consist of deoxyribose sugar, phosphate, and a base. One strand ends in a 5 prime (5') at the phosphate end, and the other strand ends at the 3 prime (3') end at the deoxyribose end.

During the semi-conservative DNA replication, the two strands separate and act as template for the synthesizes of a complementary strand where nucleotides can be added only in the 5' to 3' direction. Therefore, the formation of the leading strand is simple and continuous, as it can happen in the 5' to 3' direction.

The other strand, called the lagging strand, is formed in sections by Okazaki fragments. An RNA primer attaches itself to a point on the original template so that once again the strand synthesis can occur in a 5' to 3' direction. The last step is to remove the RNA primer and replace it with a DNA segment. This occurs in all cases except for the RNA primer at the 5' end of a strand. Here, the RNA primer is removed, but DNA polymerase can replace RNA with a DNA only between two sections of DNA segments. So after each replication, both the daughter DNAs have a shorter 5' end and a longer 3' end. If left in this condition, the longer end of the DNA would be removed by nucleases, and at the end of each replication the DNA would get shorter.

If the DNA were to get shorter than a critical point, apopotosis or cell-death would occur. The telomeres prevent this. Both telomeres and telomerase come into play now. The telomerase is a DNA polymerase that has a built-in RNA template. The first portion of this RNA template attaches itself to the 3' end, as it has complementary bases. Then, more nucleotides are added to the 3' end to complement the rest of the sequence in the telomerase. This cycle can be repeated many times to add as many sequences as are needed.

Now it is possible to add another RNA primer to the new 3' end, and the shorter 5' DNA daughter end can be completely synthesized with the help of DNA polymerase, as another Okazaki fragment. The end with the RNA primer now is part of a telomere, and remains as an overhang after the primer is removed. When this part of the telomere is destroyed by nucleases, there is no loss of genetic code.

  1. Acts as a cap

The telomeres fold back and get attached to the DNA double-helix to form a D-loop with the help of the protein shelterin. This capping is necessary to prevent DNA ends from recombining with each other and affecting genetic integrity. This shelterin also covers the telomeres and prevents the overhang from being treated as part of a DNA, and replicated by DNA repair mechanisms in the cell.

Effects of telomeres

  1. Telomerase is found in germ-line cells, where telomeres are added, and so these cells do not age. Its concentration is low in somatic cells. As these cells age, the length of telomeres decrease, leading to cell-aging and cell-death. In humans after 50-70 replication cycles, senescence follows.
  2. The rate at which telomeres are lost also depends on gender, stress, diet, and lifestyle choice like smoking.
  3. Heightened telomerase activity is found in most cancer cells, allowing them to multiply rapidly. Examples are breast, colorectal, prostate and ovarian cancers.

Possible applications in medicine

  1. Cancer treatment: If telomerase activity can be inhibited in humans, it could be used to regulate tumors in cancer.
  2. If telomerase would support unlimited cell division in human cells, it could be used to produce cells and tissues like skin or blood for transplantation.

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