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Lynch Syndrome
Lynch 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.
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.
Blooms Syndrome
A 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
Blooms Syndrome.
Ligation: The nick left in the sugarphosphate 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 Pigmentosum
is 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.