DNA Replication Errors. Failures in DNA Replication Activity Causes Mutations

DNA Structure and DNA Replication Errors

The DNA molecule looks like a twisted ladder spiraling around its long axis. The outside supports of this ladder are made up of a five carbon sugar and a phosphate group. Nitrogenous bases held together by hydrogen bonds make up the rungs of the ladder that complete the DNA structure. During the process of DNA replication, usually a new DNA molecule is created that is faithful in base sequence to the original. However, events can occur before and during the process of replication that can lead to deletions, insertions, substitutions and mismatched base pairs.

Remember that DNA polymerase copies from the template and adds nucleotides in the 5’ to 3’ direction. The enzyme adds the complementary base to the new DNA strand and proofreads before moving on to the next base on the template. The DNA structure is monitored to make sure the appropriate base pair has been added. Once an error is detected, DNA structure damage can be repaired in three different ways; mismatch repair, base-excision repair and nucleotide-excision repair.

Repairing the DNA Molecule

A mismatch repair occurs during replication of the DNA molecule when an incorrect base is found, removed and replaced with the correct one. DNA polymerase removes the incorrect base using apurinic/apyrimidinic (AP) endonuclease. The sugar-phosphate backbone section of the DNA structure must be intact, because the endonuclease corrects errors that occur with the nitrogenous base. This process adds one hundred times more accuracy to the replication process.

The insertion of an incorrect base or an additional base during DNA replication occurs when bases are misread during the process. Insertions and substitutions are caused by spontaneous chemical changes to the DNA structure. Depurination (apurination) and deamination of the pyrimidine cytosine to uracil are two types of chemical changes that can occur during DNA replication.

Depurination is the loss of a purine base by a nucleotide creating an apurinic site.

Deamination of cytosine to uracil is the loss of an amino group by the base. An apyrimidinic site is created when uracil is removed from the site by the enzyme uracil DNA N-glycosidase.

DNA replication errors that are overlooked during proofreading or fail to be repaired can result in mutations. One category of genetic mutations resulting from replication errors are the triplet repeat diseases. During DNA replication, nucleotides are incorrectly inserted resulting in regions of the DNA structure that consist of copies of three nucleotides. These sections of three nucleotides may be repeated up to fifty times and may increase in subsequent generations. Disease symptoms may appear once the number of repeats has reached a threshold level. Duchenne muscular dystrophy, fragile X syndrome and Huntington’s disease all fit this pattern.