Mechanisms of DNA Damage and Repair

Mechanisms of DNA Damage and Repair

Professor Dave again, let’s learn about
the mechanisms of DNA damage and repair. As we’ve learned,
your DNA is the template from which everything inside you is built, so it’s
incredibly important that nothing happens to this code. But your DNA is
constantly at risk of mutation, which means a change to the genetic
information in a cell, and this can happen due to a variety of factors. Let’s learn about some of the different
ways that mutations arise and what your body can do about it. First let’s make the distinction between
large-scale mutations, where a whole chunk of a chromosome is lost, relocated
or rearranged, vs. point mutations. A point mutation is typically a change in just
one base pair in a DNA molecule, and believe it or not a difference of even
just one nucleotide can be enough to cause major problems in the body. Let’s recall our prior example, sickle
cell disease. This is a genetic disorder that results
because of a difference in a single nucleotide in the DNA of a carrier when
compared to the DNA of a non-carrier. This difference occurs in the gene that
codes for one of the subunits of hemoglobin, the protein that carries
oxygen through the bloodstream. In this gene there is an A where a T should
be in the template strand of the gene, which will code for U instead of A in
the corresponding mRNA, and then this altered codon will code for valine
instead of glutamic acid. The hydrophobic side chain on valine is different enough
from glutamic acid that the mutation results in a conformational change, which
in turn causes hemoglobin to aggregate in low-oxygen conditions, forming
hemoglobin fibers. As a result, the red blood cells that carry hemoglobin will
be distorted into a rigid, sickle shape. These can clog small blood vessels, which
is a serious condition, so we can clearly see that even one point mutation can be
disastrous for an organism. When there is a point mutation one possibility is that a nucleotide
pair substitution occurs. The mutation that causes sickle cell disease is an
example of this, where one base pair is replaced with a different base pair. If
this occurs outside of a gene, it is unlikely to have any effect, because
these portions of the chromosome do not code for anything, but if this happens
within a gene, it can have a few different results. If the resulting
change in the template strand results in a new mRNA codon that translates for the
same amino acid as before, which is possible, since multiple codons can
sometimes code for the same amino acid this is called a silent mutation. In this
case, even though there was a change in the gene, the resulting protein will not
be any different. If the change in the mRNA codon translates for a new,
different amino acid, that is called a missense mutation, which is the most
common point mutation. This often won’t make a big difference either, as many of
the amino acids have similar side chains and changing just one amino acid may
have very little impact on the overall shape and behavior of the protein, but we
saw with sickle cell disease that once in a while a missense mutation might
make a big difference. Among other reasons, this can be true if the amino
acid that changed was the key residue in supplying the catalytic activity of an
enzyme. The active site might change shape due to new repulsive interactions,
rendering it unable to bind its substrate, or maybe the side chain on
this residue was specifically needed to do chemistry on the substrate, which now
can’t happen in its absence, and if that enzyme can’t do what it normally does, it
could be a big problem for the cell. So missense mutations, while often benign,
have the potential to be extremely harmful. Lastly, it is possible that a
substitution of this nature could cause the corresponding mRNA codon to no
longer code for an amino acid, but to instead become a stop codon. We call this
a nonsense mutation. This means that instead of the ribosome translating the
rest of the mRNA strand it will just stop entirely, resulting in a partially
complete protein. Unless the new stop codon is extremely close to the intended
stop codon, it is highly unlikely that this protein fragment will be able to
perform its intended function. Sometimes, instead of substitution, there can be
insertion or deletion. As you might guess this is where one base pair is inserted or
deleted from the DNA sequence. These kinds of mutations will typically have
enormous impact on the resulting protein because the codons on the resulting mRNA
are supposed to be translated as groups of three nucleotides. If one of these is
suddenly added or deleted, every single codon after this mutation will be
altered, resulting in a huge number of missense mutations, and most likely an
eventual premature stop codon. These are called frameshift mutations, because the
entire reading frame of the genetic code gets shifted. Frameshift mutations almost
always result in a non-functional protein. Now that we are sufficiently
terrified of genetic mutations, what is it that causes them to happen? Our thoughts may turn first to a glowing
green ooze, but that’s just a cliché. Let’s learn about the real causes of
mutation. The first source is called spontaneous mutation. This is when the
cellular machinery simply makes a mistake by itself, as not even mother
nature is perfect. Once in a while, polymerase will make a
mistake during replication, placing the wrong base across from the template
strand. Usually it will correct itself but sometimes it will leave the error in,
like for example this G across from a T on the template strand. This mismatch can
be recognized by one of a variety of DNA repair enzymes that scan DNA hunting for
these kinds of errors, and they know exactly which base to kick out and which
base to replace it with. This is called DNA mismatch repair. But the chromosomes
are so incredibly long that even these hard-working repair enzymes might miss an error. If this DNA
molecule is used as a template for further replication, this strand here
will do just fine, since nothing happened to it, but when replicating this strand,
the G was actually supposed to be an A so instead of coding for the T that is
supposed to go across from it it’ll code for C instead, and the GC
pair that results won’t look any different from any other GC pair in the
molecule, so no repair enzyme can ever recognize it, and the mutation can never
be fixed. This type of spontaneous mutation will happen around once in
every ten billion base pairs, which gives us pretty decent odds, and hopefully when
it happens it’s in some random location in the chromosome where it won’t make a
difference, but if it’s in a gene, who knows. Now it’s not just our heroic
enzymes that are at fault, there are external causes of mutation too, which we
call mutagens. One such mutagen is radiation. Photons of light from the
ultraviolet portion of the electromagnetic spectrum are high-energy
particles, and if they collide with DNA in specific locations they can cause
pyrimidine dimers. This is when two adjacent thymine or cytosine bases
become covalently linked, which distorts DNA, making normal genetic activity
impossible. Luckily this distortion, or lesion, can be
recognized by a repair enzyme that will initiate nucleotide excision repair. A
nuclease enzyme can spot the problem and snip out a section of the DNA strand
containing the lesion. Then polymerase puts new bases in the gap, and ligase
seals it up. Good as new. So this is why UV light from the sun can
be harmful, it may cause mutations like pyrimidine dimers. X-rays and gamma
rays can cause mutations too, since they are also comprised of high-energy
photons. Other mutations involve modifications to a singular base. These are caused by chemical mutagens
like certain oxidizing agents. For example, guanine can be oxidized to
become 8-oxoguanine, or oxoG. And because of the difference in
orientation and functionality, oxoG does not pair with C like a normal G
does, it pairs with A instead. If this error is not fixed and the opposite
strand is used as a template for replication, once again the polymerase
will have no way of knowing that this A was supposed to be a C, so instead of the G that ought to go on
the complementary strand it’ll put a T and the mutation can no longer be fixed.
Other such modifications arrive in the way of alkylating agents, which add
things like methyl groups to existing bases, which will interfere with
replication and transcription. These types of mutations do not cause kinks in
the DNA strand like thymine dimers do so they are not recognized in the same way
that nuclease enzymes operate. These are instead recognized by glycosylase
enzymes that will initiate base excision repair. This is different from nucleotide
excision repair in that the enzyme specifically recognizes the mutant base,
flips that nucleotide out of the helix and removes the base by snipping the
glycosidic bond, which is why the enzyme is called a glycosylase. Then polymerase
and ligase do their jobs to put things back together. There is a different
glycosylase for each kind of mutation of this variety and they are all
constantly scanning DNA for errors. So these are a few examples of the kinds of
damage that can occur in DNA, and while there are many more most of them fall
into one of these categories according to the type of enzyme that can repair
them. We have enzymes that can do mismatch repair, ones that do nucleotide
excision repair, and others that do base excision repair, and there are over 100
different types of DNA repair enzymes in every cell in your body, keeping constant
vigil over the sacred genetic code. Even still, let’s give him a break once in a while,
make sure you wear your sunscreen when you go to the beach. Thanks for watching, guys. Subscribe to my channel for more tutorials, and as always, feel free to email me:

82 thoughts on “Mechanisms of DNA Damage and Repair

  1. He knows all about science stuff and he is professor dave explains. This song is like gangnam style. I only watched several videos and start singing when I was cooking my dinner!

  2. So it's all about enzymes it seems. These Enzymes have cofactors. A common one is magnesium.
    Mg is at the center of the chlorophyll molecule.
    56% of US is deficient in Mg.

  3. Thank you, Professor! Does this mean that if you avoid sunlight, you will be healthier? Say if you just go in the morning sun for a few minutes, and then stay inside all the time? Or do we need sunlight so much that we can't avoid it, though it comes at a price?

  4. Not expanding on the morbid facet of nature, however molecular biology goes to show how 'surreptitious' changes can alter one's lifestyle significantly for the worse. Anyhow, wonderful video, Professor!

  5. Thank you professor…another fabulous video. I like how you go deep down into the molecular structures of the mutant amino acids and the pyrimidine dimers (and other such things) instead of just glossing over them. Getting to the chemistry at the heart of what we observe makes the learning experience so much more intuitive!

  6. Sir I m from India I want that the caption written below should be right bcs I can't understand ur language properly bt through caption I should understand your Language in better way. Nice vedio.

  7. Thank you so much Professor Dave I have an exam of Genetics this Tuesday and you have explained me about half of the themes of the exam in 11 minutes. Fantastic

  8. Thanks Dave. Good presentation! But mutations in non protein coding regions can still muck up sequences related to gene expression, right?

  9. Dude thanks for getting directly to the point and not fluffing about like so many other youtube videos. U just feed me facts that I CRAVE!!! Professor Dave 4 prime minister 2019

  10. Yeah, excuse me Professor Dave, you surely learned your DNA repar mechanisms and stuff. But can you explain why Earth is round if you have never seen it from space? Huh? I DON'T THINK SO

  11. Now that I can better understand this stuff I can see how evolution happens, but at the same time it's jerking tear from my eye because evolution found a way to make itself some repair mechanisms and this continues to blow my mind.
    As an atheist, I gotta say, it makes me feel like I'm missing something so big, so important that I even consider something as ridiculous as god.
    Anyway after seeing this it's hard to believe that we could ever find some tool that would help us target one specific point mutation at a time.
    EDIT: CRISPR can't do that, right?

  12. Do you think that if you change the dna artificialy in order to obtain a new desired characteristic (like in OMGs) the organism could try to repair the "damage" changing their structure in non certain consequences?

  13. hey there! here is my question, what is the difference between mismatch repair and base excision repair? it seems like they both send the base away. i hope you answer. thanks

  14. sunscreen is only good for preventing a serious sun burn. but beside that i do not use sun screen because it reduces the vitamin d level in the body. and with a high vitamin d level there is maybe more DNA repair going on.

  15. hey professor dave. great video! your graphics really illustrate concepts that I've been struggling to grasp since high school. this is honestly the best explanation of mutations I've ever seen. I do have one thing I wanna clarify tho. so in the frame shift mutations, it was one whole base pair that you had deleted. let's say you showed an insertion. would it be an insertion of a whole base pair? or could you have an insertion of a nucleotide on one strand but not on the other strand opposite to that added nucleotide? let me know if my question is confusing lol I'd be happy to rephrase it as best as I can

  16. How does evolution occur if this is correcting mutations all the time? And when a single point mutation gets by it it is disastrous for an organism? That doesn’t sound very promising.

  17. Dave, I suggest you first present a summarized outline using a flowchart classifying different mutations and its subtypes. This way it'll be easier to grasp and make notes at the same time. I suggest you apply it to other videos too

  18. For a layman like me this series is fairly easy to follow and understand.
    I am therefore very grateful and hope to be able to use your work here on Y-T a lot.
    Greetzzz from Holland [sorry for my bad grammar]

  19. Wireless technology creates DNA damage, apparently already after 4 hours of laptop use.
    Meanwhile wireless devices are everywhere, even if you don't have any, the office will be laced with wireless, neighbours might have a router on the other side of the wall, cell towers and so on.

    And then there's the roll out of 5G… Needless to say, we should do everything in our power to stop that.

  20. hello sir I have a question I would like to know if cancer is a gene mutation how does chemo and radiation therapy work on cancer how does it stop replication even in the begin of cancer and why after the apoptosis from chemotherapy patient has life duration depend on the stage of the cancer

  21. One big cause of gene damage is minerals and vitamin deficiencies. Too bad he left that one out. Weston Price did work in showing vitamin A deficiencies cause lack of eye development in pigs and puppies, there are pictures of this in his free online book, Nutrition and Physical Degeneration. He also showed where soil mineral deficiencies caused double faced calves and partial absorption of a twin which showed as calves with extra limbs. He even showed where calcium and Magnesium deficient soils caused proud upright horns of an ox to gradually fall when he was moved to an area of poor soil. These are things that are preventable, by supplementation, and soil supplementation. So it's sad that more isn't done in this area as it's an easy and usually cheap fix. Dolomite has calcium and magnesium, much needed by the soil for good crop production (ideal soil needs 68% calcium and 12-20% magnesium) and limestone has calcium and 60 trace minerals (found in the soils of the centenarian cultures) (soilminerals dot com). A"simple" magnesium deficiency can cause multiple illnesses and maladies including death. William Albrecht was the father of soil minerals. He discovered this and helped this farm resolve their high mortality rate.

    Also missing was a discussion of fetal alcohol and tylenol, and smoking and any number of drugs taken in pregnancy. There is enormous chance of damage in pregnancy when ingesting these things. So easy to prevent.

Leave a Reply

Your email address will not be published. Required fields are marked *