MadSci Network: Cell Biology

Re: What is the end-replication problem?

Date: Wed Jan 6 10:06:54 1999
Posted By: James Goss, Post-doc/Fellow, Neurology, University of Pittsburgh
Area of science: Cell Biology
ID: 913921894.Cb

	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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