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!
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
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)
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
Base Excision Repair: directly removes the damaged base
and replaces by a correct one
Glycosylase, removes uracil
mispaired with guanine.
is Mismatch Repair Mechanism?
is a highly sustained(from bacteria to humans) biological pathway that
maintains genetic stability.
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
times, during such processes few errors remain unattended; this is where MMR
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)
polymerase causes disincorporation of one base per 108 bases that
are synthesized, whilst MMR reduces this rate to one in every 1011 bases.
mechanism in brief:
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.
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 event, these
proteins are liable for promoting genetic variations)
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 foundation of the
most ubiquitous 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 mutat