8.4

Breast cancer

In humans, 2 genes associated with breast cancer code for enzymes that repair damaged DNA. Mutations that inactivate either gene result in a high probability (45-80%) of developing breast cancer.

Why are mutations rare

Bc cells have multiple mechanisms to repairs damaged DNA before errors are passed to offspring.

Errors in nucleotide synthesis.

DNA polymerase sometimes incorporates the wrong nucleotide when they synthesize DNA. This causes mispairing of nucleobases resulting in a slight distortion in the DNA helix which can be recognized by enzymes in the cell that repair the mistake. 2 mechanisms of this is proofreading and mismatch repair. 

Proofreading by DNA polymerase 

DNA polymerase can synthesize DNA and check the accuracy of their actions which Is called proofreading;

Proofreading

The enzymes can back yp and remove a nucleotide that is not correctly hydrogen bonded to the opposing nuclease in the template strand.The DNA polymerase inserts the correct nucleotide.

Mismatch repair

Fixes errors missed by proofreading of FNA polymerases. A specific protein binds to the site of the mismatched nuclease which directs an enzyme to cut the sugar phosphate backbone of the new DNA strand. Another enzyme degrades a short region of that DNA which removed the misincorperated nucleotide.

Hoe does the cell know which enzyme is the new one? 

If the enzyme were to cut the template strand and not the new one, the misincorperated nucleotide would still be there. To prevent this, after the strand is synthesized, an enzyme adds methyl groups to certain nucleobases. This way the repair enzyme can distinguish the 2. After the nucleotides are removed, the combined actions of DNA polymerase and DNA ligase fill that section up and seal the gap. 

What can cause base substitutions

Oxidation or other damage to nucleobases in DNA if they aren’t repaired before the DNA is replicated

Base excision repair.

Uses a type of enzyme called DNA glycosylase to remove the damaged nuclease from the sugar-phosphate backbone. Another enzyme recognizes that a nuclease is missing and cuts the DNA at the site. A DNA polymerase degrades a short section of the strand to remove the damage. The same enzyme synthesizes another strand w the proper nucleotides and DNA ligase seals the gap in the single stranded DNA.

Photoreactivation aka light repair

Mechanism to prevent DNA damaging effects of UV light. It relies on an enzyme that uses the energy of visible light to break the covalent bonds of the thymine dimer. By breaking the bond, DNA is restored to its original state.

Nucleotide excision repair

aka dark repair. Mechanism to prevent the DNA damaging effects of UV light. Doesn’t require energy fro visible light. A specific enzyme recognizes the major directions in DNA that result from thymine dimer formation then removes the DNA strand w the damaged region. A DNA polymerase and DNA ligase fill and seal the gap left by the removal of the segment.