The DNA present in a single cell of ourbody gets damaged tens of thousands of times per day and multiplying these tothe 37 trillion cells present in our body, we end up with a quintillion DNAerrors; every day!Mutation of the DNA formsthe fundamentals of evolution, but at times mutations pose to be harmful. TheDNA sequence provides the blueprint for the proteins that our cells need tofunction and thus their damage causes n number of problems, fortunately, ourcells use various enzyme-mediated ways to fix such problems. There are variousrepair mechanisms working to rectify damaged bases, strand breaks etc.
Sometimes, our DNA fails tomaintain the normal Watson & Crick base pairing, this is where DNA MismatchRepair 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 anew sequence of DNA. It removes DNAdamage 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 RepairMechanism?MMR is a highlysustained(from bacteria to humans) biological pathway that maintains geneticstability.Generally, DNA polymerasesare responsible for synthesizing new DNA strand from template DNA, by 5′ end to3′ end polymerase activity. Along with this, it also checks whether the purinesare paired with their respective pyrimidines or not, this is termed as proofreadingactivity 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 andreplace the associated nucleotide and then continue with the replicationprocess.At times, during suchprocesses few errors remain unattended; this is where MMR knocks off.It starts right afterreplication process, it is peculiar to the respective strand and along withrepair of mismatched bases it also fixes deletion and insertion mispair errorsbesides suppressing homologous recombination.(when heteroduplex DNA comprisesof extreme mismatched nucleotides)Habitually polymerase causesdisincorporation of one base per 108 bases that are synthesized, whilst MMRreduces this rate to one in every 1011 bases.
MMR mechanism in brief:This mechanism is composedof a number of proteins like SSB, DNA helicase, MutH, MutL, MutL, exonucleasesetc. The process is initiated by the recognition of the defect by the concernedproteins, 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 complexproteins chops the strand near this sequence. Exonucleases then remove thewrong nucleotide and few other surrounding bases.
This missing segment isreplaced with precise nucleotides by DNA polymerase(delta). The gap is sealedby DNA ligase. In bacteria, the parental DNA has methylgroups attached to its adenine bases, whilst the newly synthesized doesn’t,thus it can be told apart. In eukaryotes, nicks(single strand breaks) that areunique to the newly synthesized strand, are recognized by the MMR proteins.Thus the MMR proteins have the ability to discriminate between the mispairedbases, they can identify which one of the two bases should be removed andreplaced.
MMR proteins are furtherinvolved in the expansion of trinucleotide repeat (the process which forms thebasis of various hereditary and progressive neurodegenerative diseases likeHuntington disease), repair of interstrand-crosslink, class switchrecombination and even in the cellular mechanism by which the immune systemadapts to different foreign elements that attack it. (in latter event, theseproteins are liable for promoting genetic variations) Genomic instability isinduced when a mutation occurs in MMR genes. Loss of MMR results in elevatedlevels of frameshift mutation and base substitution. Studies have shown thatloss of such a repair system gives a survival advantage to the stem cells evenin the presence of DNA damage that may eventually lead to tumorigenesis.Moreover, the inherited defects in the MMR system forms the foundation of themost ubiquitous cancer syndromes in humans, Lynch syndrome(HNPCC) It is saidthat defects in MMR also leads to premature aging but no such characteristicsare observed in HNPCC patients.At times even chemotherapyleads to MMR deficiency by selective mutation of its genes.
Recently, a research wascarried out with MMR deficient and proficient strains to study their mutationpatterns, the mutation rate in the MMR-deficient strain was stupendously higherand erratically spread throughout the genome while in case of proficientstrains the mutation rate was standard and they weren’t even spreadarbitrarily. Thus it was proved that MMR mechanism also protects the crucialgenes rather than noncoding regions of the genome.