The DNA present in a single cell of our body gets damaged tens of thousands of times per day and multiplying these to the 37 trillion cells present in our body, we end up with a quintillion DNA errors; every day!Mutation of the DNA forms the fundamentals of evolution, but at times mutations pose to be harmful. The DNA sequence provides the blue print for the proteins that our cells need to function and thus their damage causes n number of problems, fortunately our cells use various enzyme mediated ways to fix such problems. There are various repair mechanisms working to rectify damaged bases, strand breaks etc. Sometimes, our DNA fails to maintain the normal Watson & Crick base pairing, this is where DNA Mismatch Repair comes in. It is one of the three types of excision repair. (Others: NER & BER)Nucleotide Excision Repair: removes a sequence of nucleotides including the damaged ones and replaces by a new sequence of DNA. It removes DNA damage induced by UV light.
Base Excision Repair: directly removes the damaged base and replaces by a correct oneEg, Uracil Glycosylase, removes uracil mispaired with guanine. What is Mismatch Repair Mechanism?MMR is a highly sustained(from bacteria to humans) biological pathway that maintains genetic stability.Generally DNA polymerases are responsible for synthesizing new DNA strand from template DNA, by 5′ end to 3′ end polymerase activity. Along with this, it also checks whether the purines are paired with their respective pyrimidines or not, this is termed as proofreading activity of DNA polymerase which is accomplished either by 5′ to 3′ or 3′ to 5′ exonuclease activity.
If any wrong pairing is detected, it will remove and replace the associated nucleotide and then continue with the replication process.At times, during such processes few errors remain unattended; this is where MMR knocks off.It starts right after replication process, it is peculiar to the respective strand and along with repair of mismatched bases it also fixes deletion and insertion mispair errors besides suppressing homologous recombination.(when heteroduplex DNA comprises of extreme mismatched nucleotides)Commonly polymerase causes disincorporation of one base per 108 bases that are synthesized, whilst MMR reduces this rate to one in every 1011 bases. MMR mechanism in brief:This mechanism is composed of a number of proteins like SSB, DNA helicase, MutH, MutL, MutL, exonucleases etc.
The process is initiated by the recognition of the defect by the concerned proteins, this can be done by uncovering the distorted sugar backbone of DNA. Then they bind to the base that has been mispaired and another set of complex proteins chops the strand near this sequence. Exonucleases then removes the wrong nucleotide and few other surrounding bases. This missing segment is replaced with precise nucleotides by DNA polymerase(delta).
The gap is sealed by DNA ligase. In bacteria, the parental DNA has methyl groups attached to its adenine bases, whilst the newly synthesized doesn’t, thus it can be told apart. In eukaryotes, nicks(single strand breaks) that are unique to newly synthesized strand, are recognized by the MMR proteins. Thus the MMR proteins have the ability to discriminate between the mispaired bases, they can identify which one of the two bases should be removed and replaced.
MMR proteins are further involved in expansion of trinucleotide repeat (the process which forms the basis of various hereditary and progressive neurodegenerative diseases like Huntington disease), repair of interstrand-crosslink, class switch recombination and even in cellular mechanism by which the immune system adapts to different foreign elements that attack it. (in latter , these proteins are liable for promoting genetic variations) Genomic instability is induced when mutation occurs in MMR genes. Loss of MMR results in elevated levels of frameshift mutation and base substitution. Studies have shown that, loss of such a repair system gives a survival advantage to the stem cells even in the presence of DNA damage that may eventually lead to tumorigenesis.
Moreover the inherited defects in the MMR system forms the root of the most widespread cancer syndromes in humans, Lynch syndrome(HNPCC) It is said that defects in MMR also leads to premature ageing but no such characteristics are observed in HNPCC patients.At times even chemotherapy leads to MMR deficiency by selective mutation of its genes.