The End Replication Problem

DNA polymerase only adds to the 3' end of a preexisting polynucleotide.
This creates a problem: the RNA primer at the 5' end will never be replaced with DNA.
If this weren't fixed, the problem would compound itself: each generation would have shorter and shorter strands, eventually deleting essential genes.

Figure 16.18, page 290, Campbell's Biology, 5th Edition

The Eukaryotic Solution

(Most) prokaryotes avoid this problem by having circular DNA molecules; the DNA polymerase simply circles around.
Eukaryotes have special nucleotide sequences called telomeres at their ends.
- Greek word derivation:
  - Telo: “end” or “final”
  - Mere: “part” or “segment”
- These are repetetive sequences that do not contain genes.
- Placing the primase in the telomere allows DNA polymerase to finish the replication at the 5' end.
- They are gradually shortened by continual DNA replication and the telomere overwriting this causes.
In humans, the repeating sequence is TTAGGG.
- 500 to 3000 repetitions, or 3000 to 20 000 bases.
- There are an additional 100 000 to 300 000 bases of telomere-associated repeats between the telomere and the rest of the chromosome.
An analogy: telomeres are like the ends of shoelaces, which protect the shoelaces from fraying but are worn off by constant use.

Figure 16.19(a), page 291, Campbell's Biology, 5th Edition

Telomerase catalyzes the lengthening of telomeres.
It contains an RNA molecule that serves as a template for new telomere segments.
Telomerase is not present in somatic cells; it is found instead in germ cells.
- Thus, the telomeres of somatic cells are shortened over time.
- Older cells have experimentally been found to contain shorter telomeres.

Figure 16.19(b), page 291, Campbell's Biology, 5th Edition

If telomeres become to short, they will trigger the cell's DNA damage detectors, which cause it to stop dividing and growing (i.e. become senescent).
If part of the DNA that codes for genes is damaged before this happens (or even after, due to complications with the process), the cell may undergo apoptosis—i.e., commit suicide.
As more and more cells in an organ enter senescence or undergo apoptosis, organs deteriorate.
- Since telomerase does not act in somatic cells, this deterioration will get worse over time.
- The process of organ deterioration with time is commonly known as aging.
- Thus, the life span of organs—or even organisms—may be limited by their telomere length.

A study done with the worm species Caenorhabditis elegans indicates that lengthening telomeres can extend life.
Another study found that increased insulin resistance (characteristic of diabetics) and weight gain were correlated with greater telomere shortening over time.
The telomeres of a certain long-lived bird species seem to lengthen as the birds grow older.

Cancerous cells are found to have active telomerase in almost all mammals.
By over-expressing telomerase, tumor cells can replicate forever without stopping.
- Without telomerase—like normal somatic cells—the tumors would eventually have to stop growing when their DNA damage detectors shut down replication after the telomeres were depleted.
- The same over-expression is found in immortal strains of cultured cells.
In a way, there is thus a tradeoff: in return for a much-decreased risk of cancer, we are cursed with aging and its diseases.