Okay. So now let's talk about some individual pathways that repair different types of specific damage. The first one is called the base excision repair or BER pathway. This pathway removes and replaces damaged nucleotides. Here is how it happens: There's an enzyme called DNA glycosylases that comes in and identifies a damaged DNA base, cutting it away from the sugar backbone. Following this, another enzyme, deoxyriophosphodiesterase, which, I know, is a mouthful, steps in. This enzyme cuts out the section of DNA that's neighboring around the base. Then, DNA polymerase comes in, fills the gap with the correct nucleotides, and finally, DNA ligase comes in to seal the gap. So here we have a damaged base in blue. Glycosylase comes in and cuts it out, more things are cut out, and DNA polymerase synthesizes that section while DNA ligase repairs and ensures everything is sealed. BER is responsible for fixing a damaged base.
We also have Nucleotide Excision Repair (NER). This repair mechanism fixes damage that distorts the double helix. We've discussed different ways the double helix can be distorted, and if it is distorted, it creates a hump that various proteins and enzymes, like polymerases, can't overcome. It has to be fixed to return the double helix to its normal structure. NER is responsible for fixing such distortions. There are two types of NER: global and transcription-coupled. The global type fixes damage anywhere in the genome, and the transcription-coupled type addresses areas near actively transcribed regions of DNA. They essentially operate in the same way, although they may involve different proteins. So, when some kind of damage occurs, proteins recognize it and recruit more proteins to the area. Eventually, around a 30 nucleotide segment is removed, DNA polymerase fills the gap, and DNA ligase seals it. Thus, the distortions are corrected. However, defects in NER can cause serious diseases, including xeroderma pigmentosum, often referred to as light allergies, though they are not truly allergies but instead a sensitivity to light. UV light, for example, causes various dimers, and without a functional NER, these dimers persist, leading to cancers and skin lesions because the body cannot repair the damage caused by light.
Finally, we have mismatch repair. This system repairs DNA damage occurring as insertions or deletions, usually immediately following replication. Here's how it works: A mismatched base, arising from an insertion or deletion, is recognized by the proteins specific for mismatch repair. The challenge, however, is identifying which base is incorrect. For example, in the sequence "TTTCGCAAGC," let's say there is an insertion that creates a mismatch. Proteins must determine whether it is the "A" or the "C" that is mismatched, and they do this based on the methylation status of the DNA. Histone proteins in DNA are methylated, but only on the old strand; the new strand, just replicated, lacks methylation. Therefore, the proteins use the unmethylated strand to determine that it contains the mutation, whereas the methylated strand is used as a template for repair. DNA polymerase then fills in the gap using the methylated strand, and DNA ligase seals it. Here, the mismatch and the methylation statuses are depicted, with proteins coming in to repair the mismatch.
These are our three major types of DNA repair. With that, let's now turn the page.