DNA Repair II
DNA Mis-Match Repair (MMR)
The DNA Mis-Match Repair (MMR) pathway has evolved to correct errors made by DNA polymerase during DNA replication. Such errors fall into two broad categories:
- base substitutions, and
- insertions/deletions.
1. A base substitution error occurs when DNA polymerase inserts an incorrect nucleotide opposite the template base, like a T opposite G instead of C, or A opposite C instead of G.
These incorrect base pairs are referred to as mismatches. Often, DNA polymerase will make an error when copying a base that has been distorted by alkylation, such as inserting a T opposite O6-methyl-Guanine on the other strand.
2. An insertion error occurs when DNA polymerase adds several extra nucleotides to a sequence; a deletion error is made when several nucleotides are omitted from a sequence. Sequences that contain repeats of the same nucleotide such as AAAAAA, are very vulnerable to these type of errors.
Other repetitive sequences, like the di-nucleotide repeat CACACACA and the tri-nucleotide repeat CTGCTGCTG, are prone to insertion/deletion errors as well. These ones are called micro-satellites.
Defects in DNA mismatch repair have been found in different types of cancer. Shorter or longer micro-satellite sequences are typical of defective MMR.
Expansion of tri-nucleotide repeat sequences is linked to various hereditary neurological disorders, like myotonic dystrophy and Huntington’s disease.
The process of MMR is like the BER and NER pathways:
- a mismatch must be recognized by a group of proteins that specialize in that particular type of distortion,
- a phospho-diester bond in the DNA strand containing the mismatched nucleotide is cleaved, then displaced by DNA helicase, and then removed,
- DNA polymerase carries out the DNA repair synthesis,
- DNA ligase restores the sugar-phosphate backbone.
The patch of DNA newly synthesized by the MMR DNA polymerase is about 1,000 nucleotides long, compared to BER, which typically replaces 1 nucleotide, or NER, which replaces about 30 nucleotides.
MMR is especially important in tissues that are constantly regenerating, like the lining of the uterus and the intestines.
Certain bacterial cells can identify invading viruses and chop up their DNA. CRISPR-Cas9 adapts that technique to allow us to edit genes nad remove harmful diseases.
Cas9 is a modified protein injected into a body to work on the DNA, like scissors that can snip the genes.
