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What is DNA repair?
DNA repair is a collection of processes
by which a cell identifies and corrects damage
to the DNA molecules that encode its genome.
Now, in human cells, damage can occur
from one of two different types of sources,
the first being endogenous, or internal, sources.
And these can come from the normal metabolic activities
that occur within the cell.
The second type of source of damage
is from exogenous, or external, sources,
and these can be any one of a number
of environmental factors.
Together, these two sources can result in as many as one
million incidences of damage per cell per day,
and so the DNA repair process is constantly active as a response
to damage in the structure of DNA.
So how is damage to the DNA recognized in the first place?
Well, damage to DNA alters the actual spatial configuration
of the helix, and such alterations
can be detected by the cell.
So as you can see here, there's a little bulge in the DNA
double helix, and that can be detected.
So once the damage is localized, this
triggers specific DNA repair molecules
to bind at or near the site of damage
and enable the repair to take place.
Now, DNA repair mechanisms can be
separated into single-strand repair mechanisms
and double-strand repair mechanisms.
And there are three main types of single-strand repair
mechanisms, and those are nucleotide excision repair,
base excision repair, and then mismatch repair.
And the method of repair that gets employed really
depends on the type of damage that
gets incurred by the strand of DNA.
Now, if a strand of DNA is exposed to UV light,
a photochemical reaction induces the formation
of these covalent linkages between adjacent pyrimidines,
such as thymine or cytosine.
Those are the pyrimidine bases.
And this yields pyrimidine dimers, which is actually
the example of the damage shown here
in the upper right corner of the screen.
Now, these pyrimidine dimers are recognized
by specific enzymes called endonucleases that cut out
the damaged nucleotides, hence nucleotide excision
repair, because the entire nucleotide is excised,
or cut out.
Then, DNA polymerase replaces the bases,
and DNA ligase reseals the gap.
Now, not surprisingly, melanoma, which is a form of skin cancer,
can occur if nucleotide excision repair fails
to fix the damage caused by UV light.
Now, if there is damage to a particular base,
then base excision repair comes into play.
Certain chemicals, like nitrates for example,
can lead to deamination of a base within a strand of DNA.
And deamination is just simply the removal of an amino group.
Now, when this occurs, base excision repair
uses specific glycosylases to recognize and remove
the damaged base, and endonuclease then
cuts the phosphodiester backbone that
is left behind at the damaged site.
And then the gap is filled by DNA polymerase
and then resealed by ligase.
And finally, the last single-strand repair mechanism
is mismatch repair, which corrects the errors that
occur in DNA replication and recombination that
lead to mispaired but not necessarily
damaged nucleotides.
Now, in bacteria, transient methylation
distinguishes the newly synthesized daughter
strand with the error from the correct parental strand, which
ensures that the repair occurs according
to the correct template.
In eukaryotes, the exact mechanism
is not quite elucidated yet.
So those are the main types of single-strand repair.
Now, let's talk about double-strand repair.
Damage that occurs to both strands in the double helix
can occur when there's exposure to ionizing radiation,
such as gamma rays and x-rays.
And just like there are three main mechanisms
for single-strand repair, there are three main mechanisms
of double-strand repair.
And they are non-homologous end joining,
microhomology-mediated end joining,
and homologous recombination.
Now, in non-homologous end joining,
a specialized DNA ligase forms a complex
with a cofactor that directly joins
the two ends and the break ends are directly
ligated without the need for homologous template.
Now, when I say homologous, I'm referring
to a similar linear sequence of gene loci,
and the same goes for whenever I use the word homology.
It's any two DNA sequences that have similar gene loci.
Now, microhomology-mediated end joining
works by ligating the mismatched hanging strands of a DNA,
removing the overhanging nucleotides,
and then filling in the missing base pairs.
So when a break occurs, a homology
of, say, 5 to 25 complementary base pairs on both strands
is identified and then used as a basis
for which to align the strands with the mismatched ends.
Once aligned, any overhanging bases, or flaps,
and mismatched bases on the strands are removed,
and any missing nucleotides are inserted.
Now, finally, homologous recombination
requires the presence of an identical or nearly-identical
sequence to be used as a template
for the repair of the break.
And this pathway allows a damaged chromosome
to be repaired using a sister chromatid
or a homologous chromosome as a template.
The enzymatic machinery that's responsible for this repair
process is nearly identical to the machinery
responsible for chromosomal crossover that
occurs during meiosis.
And so that is it for double-stranded repair
mechanisms.
Now, the actual rate of DNA repair
is dependent on a lot of factors,
including the cell type, the age of the cell,
and the extra-cellular environment,
just to name a few.
And a cell that has accumulated a large amount of DNA damage
or one that can no longer effectively repair
the damage incurred to its DNA can
enter one of three possible states.
Now, the first one is an irreversible state
of dormancy known as senescence, and you can kind of
think of the cell in this case as going into a hibernating
mode.
And the second possible state is known
as apoptosis, or programmed cell death.
And then the third possible outcome
is unregulated cell division, which
can lead to the formation of a tumor that
can become cancerous.