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 blueprint 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
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 one
Eg, Uracil Glycosylase,
removes uracil mispaired with guanine.
What is Mismatch Repair
MMR is a highly
sustained(from bacteria to humans) biological pathway that maintains genetic
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
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)
Habitually 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 remove 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 the 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
MMR proteins are further
involved in the 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 the cellular mechanism by which the immune system
adapts to different foreign elements that attack it. (in latter event, these
proteins are liable for promoting genetic variations)
Genomic instability is
induced when a 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 foundation of the
most ubiquitous cancer syndromes in humans, Lynch syndrome(HNPCC) It is said
that defects in MMR also leads to premature aging but no such characteristics
are observed in HNPCC patients.
At times even chemotherapy
leads to MMR deficiency by selective mutation of its genes.
Recently, a research was
carried out with MMR deficient and proficient strains to study their mutation
patterns, the mutation rate in the MMR-deficient strain was stupendously higher
and erratically spread throughout the genome while in case of proficient
strains the mutation rate was standard and they weren’t even spread
arbitrarily. Thus it was proved that MMR mechanism also protects the crucial
genes rather than noncoding regions of the genome.