|MadSci Network: Cell Biology|
Sorry about the length of time it took me to answer this question, with the hussle and bussle of the holidays, I completely forgot about it. Anyway, the end-replication problem is a fundamental problem associated with replicating linear DNA. As you know, DNA is a molecule made up of two strands of nucleic acid subunits. The "direction" of a strand of DNA is determined by how these nucleic acid subunits are attached. The structure of a nucleic acid has as its backbone a ribose, or 5 carbon sugar, and nucleic acids attach to one another (via a phosphodiesterase bond) between two of these carbons, the 5’ carbon and the 3’ carbon. The two strands of a DNA molecule are antiparallel to one another. This means that one strand runs 5’-3’ while the complimentary strand runs 3’-5’. Now, the problem we run into is during replication of DNA. DNA replicates using an enzyme complex known as DNA polymerase. Replication is semi-conservative in that the two strands of DNA are separated and each (we will call these the mother strands) are used as a template for a new strand of DNA (called the daughter strand). New strands of DNA are formed as the mother strands separate, much like a zipper Unfortunately, DNA polymerase can only make DNA in a 5’-3’ direction and it needs a "primer". This primer is a small piece of RNA which attaches to the mother strand of DNA, thus giving the DNA polymerase a place to start. All of this is ok for the 3’-5’ mother strand because it is a perfect template for the DNA polymerase, but the 5’-3’ mother strand is a problem. How do you synthesize the 3’-5’ daughter stand when your enzyme will only go 5’-3’? The answer is that you synthesize in small pieces as the mother strand is unzipping (any genetics textbook and most biological texts will have a good illustration of this). Thus we have one daughter strand which is synthesized as a continuous piece of DNA (called the leading strand) and one daughter strand which is synthesized in small, discontinuous pieces (called the lagging strand). At the extreme end of the DNA, we run into a problem. The leading stand can be made to the very end, but the lagging strand cannot. Remember that you need the RNA primer to begin each piece of the lagging strand DNA, but at the end of the DNA there is nothing for this piece to attach to thus the last section of the lagging strand cannot be synthesized. You can see that after several rounds of DNA replication, the DNA molecule would continue to get smaller and smaller. Well, biology has solved this problem by putting a "cap" on the ends of DNA. This cap is called the telomere and it is a large piece of DNA which does not code for any protein. The enzyme telomerase extends the leading strand DNA synthesis into the telomere. This extended leading strand now provides the necessary template for completing synthesis of the lagging strand by DNA polymerase. Now, with aging you have a couple of problems. First, as the DNA is replicating over and over, the telomere becomes shorter and shorter. Since one of the functions of the telemeres is to stabilize the DNA (i.e. chromosomes), as these shrink with age, the chromosomes become less stable, leading to cellular dysfunction. Second, the telomerase enzyme itself becomes less stable with age (as do many enzymes). This causes more problems with DNA replication and stability.
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