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10. Beskrive telomere samt hvordan og hvorfor de bliver repareret. Angive at de fleste humane kræftceller indeholder aktiv telomerase mens normale somatiske celler (undtagen stamceller) ikke gør.
Devlin, s.181, fig 4.17
Stryer, s. 765-6, fig.27-35
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/T/Telomeres.html

Telomeres are special structures on the end of eukaryotic linear chromosomes, which contain many repeats of a six-nucleotide, G-rich repeat sequence.

Human telomeres contain hundreds of tandem repeats of the sequence TTAGGG. The 3´-end of one strand of the chromosome extends about 18 nucleotides beyond the strand with 5´-end, leaving three repeats as an overhang. 

The overhanging 3´-end folds back on itself and makes G-G hydrogen bonds. It also binds extra proteins that define the chromosomes length and protect it from recombination (since the ends of the DNA molecule tend to trigger recombination). 
 

Telomeres are replicated and maintained by telomerase, a ribonucleoprotein complex that adds six-nucleotide repeats to the 3´-end of a telomere. Telomerases are specialized polymerases that carry their own RNA template.

The telomerase binds complementary to the template strand with the 3`-OH ending, binding a part of its RNA sequence with hydrogen bonds to the last few nucleotides of the template strand.
 

• Telomerase RNA then acts as template for the reaction

• The protein part of the enzyme acts as a reverse transcriptase, which synthesizes DNA using RNA as a template.

After 6 nucleotides are added, the telomerase can disassociate and bind again, adding 6 extra nucleotides for each time it binds.  

Telomeres do not have to remain exactly the same length. Shortening is not a problem as long as the lost sequences do not encode proteins.

So, the cells need to maintain and repair their telomeres, in order not to lose gene coding sequences localized towards the end of the chromosome.

Cells that have differentiated and no longer divide, or will divide only a limited number of times, do not express telomerase; it is turned off during embryonic development. Somatic cells in the human body do not have active telomerase and the chromosomes shorten 50 base pairs for every cell division.

If cells from a new born baby are cultivated in the lab and left to divide, they would divide around 100 times and then die. A 70-year old men cell would divide only dozen times before they die. In the last case, the telomeres are already extensively shortened and it does not take long before gene-coding sequences are lost.

That is why telomeres are associated with aging.

Telomerase is expressed in:

• Embryonic stem cells - these cells are rapidly dividing and differentiate. Telomerase therapy can be used in exhausted stem cells; it can renew their ability to divide. 
   

• Cancer cells - these cells produce abnormally high levels of telomerase. The enzyme is found freely flowing in the nucleus. Thus, cancer cells can multiply at will and divide a lot of times without losing coding sequences. That is why telomerase in these cells is an attractive target for chemotherapy. Still, the effect would be delayed by many cell cycles. 

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