Sunday, September 2, 2012

DNA Damage Repair

As a fresher in University starting this year, I have received a preparatory reading list useful for me to go through before arriving in University. All the books are due to cover the basic principles of Biochemistry, representing the course that I'll be reading at the University of Oxford, but also Organic and Physical Chemistry.

As I am currently reading a chapter concerning the flow of genetic information, I found out how the cell is responsible for the maintenance of the DNA, an essential feature without whom the cells would suffer chaotic mutations and potentially hazardous transformations.

It turns out, that there are two ways through which the DNA gets damaged. First, there is the danger of "misspelling" a nucleotide during replication. For this, the cell has a system of post-replicative mismatch repair that corrects the eventual errors appeared in the replication of DNA by polymerase.
During cellular division, DNA replication takes place at a speed of about 50 nucleotides per second, leaving almost no room for error. In other words, post-replicative mismatch repair is the "proof-reading" technique used by the cell. Incompatible pairs of nucleotides are identified, the parent strand is kept, while the daughter strand is cut and re-synthesised by DNA Polymerase.

With this "proof-reading" technique, errors still slip at a rate of about 1/107. Still, there are other factors that contribute to the damaging of the chromosomal information, such as UV degradation, normal cellular activity, hazardous chemicals, etc.

For instance, UV damage causes the dimerization of adjacent pyrimidinic nucleotides in a process as follows:

The formation of a Thyminodimer out of two T adjacent nucleotides

The dimers are removed and replaced by excision repair using a special protein (Excision Repair Nuclease) that identifies the affected area (by geometric abnormal conformation), excises the malfunctioning DNA, fills the gap using a polymerase and then joins the bits together with a ligase.

Another common form of degradation of DNA is the transformation tautomerization of nucleotides of by their natural degradation in the cell.

The transformation of Cytosine (C) into Uracil (U) as part of DNA Damage

In this case, the DNA strands are repaired by employing a technique called Base Excision Repair (B.E.R.). In the process the damaged base is first removed. Using the aid of an endonuclease, a gap is made into one of the two strands that are comprised within the helix structure. An exonuclease will enlarge the gap, also removing adjacent nucleotides in the process. Then, DNA polymerase fills the gap, and ligases bind the fragment into place.

These two extra mechanisms further reduce the incidence of errors in the genetic code to a rate equal to 1/109, which is 1 error in one billion replicated nucleotides, thus making the damage repairs 100 times more precise. As a matter of fact, the whole human genome is appreciated to be 3.2 billion nucleotides long, according to the study "Parameters of the human genome" by N. E. Morton, published in 1991.

In conclusion, given the 1/109 incidence rate of errors in DNA, every human has a rate of about 3.2 mutated or erroneous nucleotides per the entire genome, which is very little given the fact that all proof-reading is performed through only these three above mentioned mechanisms at incredible speeds.

1 comment:

  1. While a lot of DNA contains information for a certain function, there is some called junk DNA, which is currently used for human identification. At some special locations in the junk DNA, predictable inheritance patterns were found to be useful in determining biological relationships.