DNA Mismatch Repair System (MMR)MMR is a cell’s mechanism for recognising and correcting mistakes made during DNA replication. Errors made during DNA replication will be located on the ‘daughter’ strand, which the MMR system distinguishes from the parent strand using an unknown mechanismwhich may have to do with ‘nicks’ left in the newly-synthesised DNA. After identifying the daughter strand, the following proteins are used to correct the mismatched bases: MutSα – This protein complex recognises and binds to misincorporated basesMutLα – This endonuclease complex nicks the DNA strand at sites around the mismatchEXO1 – This exonuclease removes the resulting DNA segment in conjunction with RPA’sDNA Polδ – This polymerase re-synthesizes the gaps in the strand with the correct baseDNA Lig1 – This ligase finally reseals the repaired segment into the strand Lynch SyndromeLynch Syndrome, also known as Hereditary Nonpolyposis Colorectal Cancer (HNPCC), is a genetic condition which predisposes people to a number of cancers. It is caused by mutations in the MLH1, MSH2, MSH6, PMS2, or EPCAM genes, which impair the activity of the Mismatch Repair proteins. This results in microsatellite instability in the DNA, causing it to accumulate errors. This leads to an increase in mutations during DNA replication, which particularly increases the risk of colorectal cancers (50-80%). It also increases the risk of cancers of the endometrium (20-60%) and ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin.

Homologous recombination repair

Mostly used to repair breaks that occur on both of the DNA strands, breaks that are also known as Double Strand Breaks (DSB)Needs an identical or almost identical sequence to be used a template for the repair, hence the term homologous, as it will only occur between double stranded polynucleotide molecules that hold large sections of similar sequence.

The Process 2 DNA molecules, one with the DSB and one without, are positioned close to each other A nuclease creates single stranded ends at the DSB by paring back the strands so that both strands contain a 3’ single-stranded tail.Strand invasion occurs and a branch point is created, when one strand from each DNA duplex cross over each other, and extensive base pairing occurs between the two. Branch migration occurs and the strand created from the DSB is elongated by a repair DNA polymerase, and the complementary strand is used as a template for the DNA synthesis which is followed by DNA ligase.

Bloom’s SyndromeA disease characterized by a predisposition to cancer, unstable genetic material, short stature and a rash which can develop after exposure to sunlight. Identified by an increased frequency of sister chromatid exchanges, it is a recessive disorder. A defect in the homologous recombination repair process can result in a mutation of the BLM gene, which causes Bloom’s Syndrome.

Nucleotide Excision RepairNucleotide excision repair is the most basic mechanism of DNA repair. It is composed of 3 steps:· Excision: The damage is cut out of a series

of nucleases; one at a time, each specialized for a type of DNA damage.

· Resynthesis: A repair DNA polymerase restores the original DNA sequence therefore filling in the gaps created by the excision events.

· Ligation: The nick left in the sugar-phosphate backbone of the repaired strand is sealed by DNA ligase.

The broken phosphodiester bonds between the neighboring nucleotides are reconstructed by nick sealing which requires energy from ATP hydrolysis.Some types of DNA damage involve the replacement of a single nucleotide. However, other kinds of DNA damages like thymine dimers (a longer stretch of 10-20 nucleotides) are removed from the damaged strand. Xeroderma Pigmentosumis an autosomal recessive genetic disorder of DNA repair in which the ability to repair damage caused to thymine dimers by ultraviolet (UV) light is deficient. An individual with this disorder has inherited a defective gene for one of the proteins involved in this repair process. As a result they develop severe skin lesions including skin cancer because of the accumulation of thymine dimers in cells that are exposed to UV light and the consequent mutations that arise in the cells that contain them.