Repairing damaged DNA:  Mistakes are made during DNA synthesis and DNA can be damaged by environmental factors, which include radiation, ingested chemicals and reactive compounds made by the cell itself.

Moreover, in aqueous solutions, DNA is not completely stable.

For example, cytosine can react with water, which is present at a concentration of ~55 M inside a cell.  

It undergoes a deamination reaction to form uracil.

Uracil is not normally found in DNA, so it easily recognized as a mistake by the enzyme uracil-DNA-N-glycosidase. 

This enzyme severs the tie between the base and the deoxyribose group.

This reaction is similar to a process that can occur spontaneously, that is without an enzyme. The bond between the base and the sugar can be hydrolyzed and the base is lost.

Each cell undergoes ~10,000 base loss events per day or ~10¹⁸ events per day per person. That's a lot!

The absence of a base, due either to spontaneous loss or enzymatic removal acts as a signal for the enzyme AP (absent purine/absent pyrimidine) endonuclease.

This enzyme cuts the bond between sugar and phosphate of the DNA strand, and digests back a short length of DNA in the 3' to 5' direction.

A DNA polymerase binds to the open DNA and, using the undamaged strand as a template, fills in the gap.

This general system is known as Base Excision Repair.  In the human genome there are over 130 genes devoted repairing damaged DNA.

• I thought RNA primers were used to make DNA! So why is there no uracil in a DNA molecule?
• A base is lost, how is this loss recognized by repair systems?

Mutations & disease:   Mutations the ultimate source of genetic variation - without them evolution would be impossible.  

When they are the essential for evolution, defects in DNA synthesis can lead to a number of diseases. For example, the trinucleotide repeat disorders.

These diseases are caused by slippage of DNA polymerase and the subsequent duplication of sequences.

There are diseases that involve such repeats .

When these slipping repeats occur in a region of DNA encoding a protein, it can lead to regions of a repeated amino acid.

For example, expansion of a domain of CAGs in the gene encoding the polypeptide Huntingtin causes the neurological disorder Huntingdon's chorea.

Fragile X:  This replication defect is the leading form of autism of known cause. Sadly, there are many forms of autism in which the cause is not known.

Only about 6% of all autistic individuals have fragile X.

Fragile X can also lead to anxiety disorders, attention deficit hyperactivity disorder, psychosis, and obsessive-compulsive disorder.

Because the mutation involves the FMR-1 gene, which is located on the X chromosome, the disease is sex-linked and effects mainly boys.

In the unaffected population, the FMR-1gene contains between 6 to 50 copies of a CGG repeat.

Individuals with 6 to 50 repeats are phenotypically normal.

Those with 50 to 200 repeats carry a premutation; these individuals rarely display symptoms but can transmit the disease to their children.

Those with more that 200 repeats typically display symptoms and often appear to have an apparently broken X chromosome - from which the disease derives its name.

The pathogenic sequence in Fragile X is downstream of the FMR1 gene's coding region.  When this region expands, it inhibits the activity of the gene.

Defects is DNA repair can lead to severe diseases and often a susceptibility to cancer.

For example, defects in mismatch repair lead to a susceptibility to colon cancer, while defects in translation-coupled DNA repair are associated with Cockayne syndrome.

People with Cockayne's syndrome are sensitive to light, short and appear to age prematurely.

• Do defects in DNA repair alter the rate of DNA polymerase induced mutation?
• What happens in cells with defects in DNA repair systems when they attempt to divide?