Understanding DNA Replication: The Science Behind Cell Division
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Introduction
As we delve into the fascinating world of molecular biology, one of the most pivotal processes you’ll encounter is DNA replication. This intricate mechanism not only enables the reproduction of genetic material but also plays a crucial role in cellular division, which lays the foundation for growth and maintenance in living organisms. In this comprehensive guide, we will explore the fundamental principles of DNA replication, illuminating its purpose, phases, and the enzymes involved in this biological symphony.
Why Do We Perform DNA Replication?
DNA replication is essential for life as it allows cells to make copies of their genetic material so that they can reproduce. But before we dive deeper, let's clarify its overarching goal:
- Cell Replication: The primary purpose of DNA replication is to ensure that when a cell divides, each daughter cell receives an identical copy of the DNA. In humans and many eukaryotic organisms, this process is intricately linked to the cell cycle, which phases through G1, S, G2, and mitosis.
- Significance of the S Phase: It is crucial to understand that the actual replication of DNA happens predominantly during the S phase (Synthesis phase) of the cell cycle.
Key Principles of DNA Replication
To fully grasp the mechanism of DNA replication, it’s vital to discuss some foundational concepts:
Semi-Conservative Model of Replication
DNA replication follows the semi-conservative model, in which each of the two strands of the double helix serve as templates for the production of complementary strands. Here’s how it works:
- Each original strand serves as a template.
- New strands are synthesized alongside the old strands, preserving one original strand and generating one new strand for each helix.
Directionality in DNA Replication
The direction of DNA synthesis is paramount:
- 5’ to 3’ Direction: DNA replication can only proceed in the 5’ to 3’ direction. This means that nucleotides are added at the 3' end of a growing strand.
Bi-Directional Replication
DNA replication occurs simultaneously in both directions from the origin of replication, creating forks at which the two strands separate. The process is highly organized:
- Replication Forks: These Y-shaped regions occur at both ends of the DNA, with the enzyme helicase unwinding the strands ahead of the replication process.
Steps of DNA Replication
The DNA replication process can be broken down into three major stages:
1. Initiation
Initiation of DNA replication begins at specific locations called origins of replication. Here are key components involved:
- Pre-Replication Protein Complex: This complex binds to the origin and begins to unwind the DNA strands.
- Replication Bubble: The area that forms as the DNA unwinds, resulting in two strands available for replication.
- Single-Stranded Binding Proteins (SSBPs): These proteins bind to the separated strands, preventing them from re-annealing.
2. Elongation
Once initiation is complete, the elongation phase occurs:
- Primase: This enzyme synthesizes short RNA primers necessary for DNA polymerases to begin building new DNA strands.
- DNA Polymerase III: The primary enzyme that synthesizes new strands of DNA by adding nucleotides in the 5’ to 3’ direction. It reads the parent strand from 3’ to 5’. The leading strand is synthesized continuously, while the lagging strand is formed in segments known as Okazaki fragments.
3. Termination
Termination occurs when the DNA polymerases reach the ends of the DNA molecule. In eukaryotic cells, there is a special concern with the very ends of chromosomes, called telomeres:
- Telomeres protect chromosome ends from deterioration but shorten with each replication cycle.
- Telomerase can extend these regions, ensuring that vital genes are not lost during cell replication.
Proofreading and Error Correction
Throughout DNA replication, high-fidelity is maintained:
- DNA Polymerase III possesses proofreading capabilities that allow it to excise incorrect nucleotides and replace them with the correct ones.
- Any errors made during synthesis are corrected in real-time, significantly reducing mutation rates.
Conclusion
DNA replication is a complex yet fascinating process that showcases the intricate workings of cellular machinery. Understanding the significance of this process provides crucial insight into genetics, molecular biology, and the mechanisms of cell division. From initiation to termination, each step is meticulously orchestrated, ensuring that genetic information is accurately passed on. As research continues to unfold, the implications of DNA replication extend into fields such as cancer research, genetic disorders, and therapeutic interventions.
By comprehending the essentials of DNA replication, we can appreciate the miracle of life at its most fundamental levels, thus reinforcing the connection between molecular mechanisms and the broader biological systems.
In summary, DNA replication is a semi-conservative, bi-directional, highly regulated process with immense significance in the cellular lifecycle, ensuring that life perpetuates through faithful genetic transmission.
what's up ninja nerds in this video today we're going to be talking about dna replication but before we get
comment section and please subscribe also down in the description box we have links to our facebook instagram patreon
account go check that out all right ninja nerds let's get into it all right ninjas when
we talk about dna replication the first thing that we need to talk about is a couple of fundamental points very
important things that we're going to build on throughout the process of this lecture and so the first thing i need
you guys to know is what in the heck do we do dna replication for and the whole point is is that in order
the genetic portion of the cell it's what makes a cell what it is so in order for us to really
okay so the cell cycle i know you guys know the cell cycle when in the cell cycle what's kind of
the really quick part of it you start off you go g1 then you go s phase g2 phase and then you go into
that cell enters into the g1 s g2 goes through mitosis and makes two cells the big thing i want you to know is that
dna replication primarily occurs within a particular part of the cell cycle when a cell's replicating making more cells
it primarily occurs within the s phase so in the s phase that is where dna replication is occurring so the first
fundamental that you need to know is why do we perform dna replication in order for our cells to replicate make
dna is actually replicating is in the s phase of the cell cycle now real quick what in the heck is cell
replication it's really simple i'm taking this cell here which has 23 maternal and 23 paternal chromosomes
and all i'm doing is i'm making two identical cells that look just like this so i have to replicate
the dna within this chromosome and the dna within this chromosome and i'll make two of this
and two of this and that's going to give me these two identical daughter cells and that's the basic process of cell
semi-conservative means let's take that a piece of dna here right so dna has two strands and we're going
to call these we're going to give them two names we're going to call these blue dna
strands parental strands or let's call them old strands what i'm going to do is when i want to
replicate this dna i have to separate them and we'll talk about how we do that when you separate the dna into separate
this was g this would be c if this was c this would be g you get the point i'm going to make
different and i synthesized a new strand or a a daughter strand if you will that's one aspect of it i'm
going to do the same thing to this other strand so i'm going to use this old parental strand
and make a new strand with complementary nucleotides on the other old parental strand i'm going to again
make dna that is complementary to this old or parental strand so the whole concept here is that i start with
two old parental strands separating them and making two new dna strands that are complementary to them
process the next really important thing that you guys need to know is that dna replication occurs in a very
very specific direction dna replication has to occur okay the direction okay replication direction
is very important it's kind of annoying we'll mention it a lot throughout the process of this lecture
end i can't stress that enough super important it's going to come up a lot what the heck does that mean really
quickly do you guys remember from the dna structure video what was on the five prime end of a
nucleotide the phosphate group what was on the three prime end of the nucleotide the oh group
group of the preceding nucleotide let's show you an example of that so let's say that we took this old dna
strand we're gonna do replication following the semiconservative model here i have two old parental dna strands
separate them i'm going to replicate it via the semiconservative model but i'm also going to follow this
process where i have to replicate five to three so let's say on one end of this old dna
strand i have a three prime end here what does that mean that means there's an o h group here on
oh group and then the phosphate group right here so that's basically what the five prime three prime end is
and you guys remember that dna is antiparallel so if it's three prime on one end five prime on the other
it's three prime and three prime on the same end that it was five prime that's important
so when dna replication occurs it has to occur five to three so here's the three prime end
and then what will i do i'll add another nucleotide and then this connection here will be
between what i'll have a three prime end here and a five prime end of this next nucleotide
i'll have a three prime end here i'm gonna add another nucleotide so when i make nucleotides i make them
this strand here's the five end here's the three end of the parental strand if i want to make the new strand
okay so that's the important thing i need you guys to remember is that dna replication occurs in a five to
to know that i think oftentimes when we're looking in textbooks we only focus on one end where dna
replication is occurring but what's really important is we're going to talk about this in a second but
what we do is we take the dna and we already have an idea that we're going to separate the two older parental strands
away from one another so that we can create new dna from that when we do that we create these little
ends here these little y-shaped regions called replication forks okay so it's called the replication fork
and you have two of them one on this end one on this end there's going to be enzymes called
which we'll talk about they're also going to move into these areas and follow the helicase synthesizing new
so the big fundamentals i need you guys to take away is that why do we do it dna replication in order for cells to
making a mixed old and new double two double-stranded dna molecules it occurs in a five to three direction
and it occurs bi-directionally from what's called the origin of replication or where these
replication forks are okay now that we have the fundamentals let's now talk about the steps of dna
about the stages of dna replication there's three stages of dna replication initiation elongation and termination
it's not too hard to remember so what happens is let's say that here i have my double-stranded dna okay and
really really a nice little area that i want to go and i want to separate the dna so that i can
create two separate dna strands parental strands that i can use as templates to make new dna
that area is going to become our origin of replication all right so this area is really what's
so whenever we need we're picking this spot how do we determine what that we're picking that spot like okay i know
nucleotides in this region which are really highly concentrated with adenine and thymine so it's an adenine
why would i pick adenine and thymine as the area that i really want to target as compared to
bonds are there between them two how many hydrogen bonds are there between guanine and cytosine
three it's going to be easier to break two hydrogen bonds and it is going to be able to break three hydrogen bonds
so in this area there's going to be particular areas which are really concentrated with adenine and thymine
nitrogenous bases or nucleotides and that's going to be better suited as the area we want to
compared to guanine and cytosine okay so that's the first thing we have particular areas now
thymine i just have enzymes bind to that portion and separate it and the enzymes just work from the
center and go to the ends no what's really important that you guys need to know is that in eukaryotic cells
so that's really really important so for example i may just be representing this one portion but there may be another
origin of replication right here and another origin of replication here which is really rich in adenine thymine
nucleotides okay so that's one important thing the next thing is what type of structure
is going to bind onto these areas and help to break the bonds between the adenine and thymine
what do we have there's a really interesting protein it's got one heck of a name they always
pro pre-replication protein complex one heck of a name so here we're going to draw a cute
little enzyme here okay this is a cute little enzyme and this enzyme is going to come in and
the adenine and thymine nucleotides in that area to separate the dna what is this protein here called that
uh nitrogenous bases now once it does that what's that going to look like well let's take the next step
we had this protein bind on to the origin of replication where there's a lot of adenine and thymine nucleotides
we separated the bonds between them the two hydrogen bonds and we create this little like bubble if
you will you know what we call this it's not hard it's called the replication bubble that's literally what
it's called i know it sounds crazy but now we kind of form this little bubble due to this whole process and
it's called the replication bubble now once we form this replication bubble there's a couple things that i
need you guys to know we have separated the nucleotides so if you imagine here we're not showing them but let's say
that here i show a couple you know here's my nitrogenous bases that are coming off this
sugar phosphate backbone right which is made up of again the deoxyribose sugars the phosphate groups
so i'm going to have these exposed now so these were once really connected nicely together like in
these regions i really separated them so they're really kind of like vulnerable right now and you know what's
to re-anneal with one another all right so what is this protein that really helps to protect
you know it's really ironic uh you know sometimes science is there's a big old protein
that comes and binds to this end it would do the same thing on this one and this protein you know what it's
called it's called the single stranded binding protein i'm not even joking that's literally the name of it
and it's perfect it's not hard to remember why because it's a protein binding to a single
parental strand so you would have one over here i'll just draw a portion of it but you'd have the same thing over here
another single strand of binding protein binding onto this parental strand and what is the purpose of these single
stranded binding proteins that's what i really want you to remember one of the functions is that it prevents
the parental strands from re-annealing what the heck does that mean what's that term re-annealing from reconnecting to
these uh parental strands separated as kind of these single strands if you will they're very vulnerable to very nasty
little enzymes there's some nasty little pac-man-like enzymes that want to come to the area
and break the phosphodiester bonds these are called nucleases so what these single-stranded
okay so so far free replication complex binds to the origin of replication or the at rich area separates it forms a
replication bubble single strand of binding proteins bind to the single strands prevent them from
kneeling and protect them from nucleases the next thing is once you form a replication bubble you form these two
this end here where it kind of like makes like a y shape if you will this right here is called your
replication fork okay there's going to be an enzyme that we're going to talk about in just a
in these replication forks unwinding the dna in front of them this enzyme is called helicase
and the big thing i really want you to know about the helicase enzyme is that he requires a ton of atp
complex binds to the origin of replication at rich area separates it single-stranded binding proteins bind
that we definitely need to know let's come down here and this is a really important area that i really really need
again what we have binding right here to these two ends single stranded binding proteins we're
not going to show it on the top but the same thing here and then again what enzyme let's just
focus on this area right here just on this replication fork what enzyme would be in this area here
what happens is as helicase continues to unwind the dna the whole purpose of that as it unwinds the dna separates the
okay but there's a problem that happens as dna helicases just you know going through those mofos and unwinding the
dna constantly in front of it it bunches up the dna in front of it distal to it okay from that replication
fork so distal to the replication for downstream the dna starts bunching up and it creates things these things
and this is caused by the helicase really unwinding the dna why are super coils bad if you really
bunch up the dna in front of it it's going to really impede the helicase from continuing to unwind the dna it's
going to face a lot of restriction because it's really bunched up here so it'll just keep getting bunched up until
in there and fix these supercoils where the dna is really really tightly wound so how do we
these guys are really cool and they are called topo high sama races they're shape of the t
couple different types okay there's particularly type 1 type 2 and then there's type 4.
for the most part they all do the same kind of thing and what is that okay this enzyme has two little
arms if you will let's say here it has one little arm and another little arm on one arm
it can go to where this area of the supracoil is let's say that the supercoil's right here
if it cuts the dna strand what does that allow for it to do it kind of allows the dna to kind of
unwind a little bit and unravel and so there's a particular name to this domain on that
allows it to unwind there's a problem with that though if i just cut the dna strand and allow
i don't want that so what i do is i use this other arm and after the dna super coils have been alleviated so
that's a problem so now we need to use the other arm of this topoisomerase where we cut
it re-stitches this area back together after it's unwound the super coils okay so again the topwise sama races
why in the heck did i take all this time to mention the topoisomerases and there's different types
let me explain why topoisomerases can be in both cells so we primarily haven't really discussed
that dna replication can occur in bacterial cells and it can occur in eukaryotic cells or we call it bacterial
does not require any atp to unwind the supercoils so let's put that next to it that just for this one just for this one
coils there's also one more thing i don't want to get too far in depth in it that type two and four can do that are a
little bit different from type one and that's that if you really look in the the textbooks
insert in what's called negative supercoils which also helps to kind of relax the dna and
prevent that kind of bunching up region let's not get too far into depth in that what i really want you guys to know
is why in the heck did i spend so much time talking about these topoisomerases in your usmles you have to know
in eukaryotic cells when this is important for dna replication if these enzymes aren't really working
so if i have cancer the cells will continue to replicate so they'll replicate and replicate and
replicate well i could maybe use some drugs that could target these topoisomerases in my cancer
well there is a particular name of there's a couple drugs that you guys definitely need to know
topoisomerase one in the cancer cells the type two in eukaryotic cells we can use drugs called etopocide
and tinopocide and i'm going to explain how they do that because that's really important i really want you to
understand how they do this but that's for the eukaryotic cells think about prokaryotic cells
if you were infected by a bacteria and a bacteria infected your lungs and it just kept replicating and
replicating within your lungs could i maybe target the topoisomerase two and four and prevent that replication
process of the bacteria in my lungs yes so in bacterial infections let's say because it's a prokaryotic
so if i use particular drugs that can maybe prevent the dna from replicating in these bacterial cells
the topoism race too but i really want to take a second because i never understood this completely until i
really dug into the mechanism of how they actually do this i really want to quickly say how they do it
they're exciting in increasing the activity of the nuclease domain what the heck is that going to do that's
going to just chop all those like portions of the dna and it's going to continue to fragment them
kind of stitched it back together to prevent that fragmentation that was the ligase binding domain what
i'm going to have this enzyme go in and kind of cut where the supercoils is but i'm never going to re-stitch it
together the dna will just fragment over time and that's important because then you can't replicate the dna
within what kind of cells eukaryotic cells like cancer cells or bacterial cells and that's why those
so we kind of went through talked about the topoism races that was the big thing and how they
unwind the super coils let's get back to the foundational science and now that we've talked about
nerds so we already know we have a replication bubble we got a replication forks we have our
protein here called the single strand of binding protein which is stabilizing these single strands
we have the helicase enzymes that are in these replication forks working like a son of a gun
to unwind the dna we've got those topoisomerases over here that are kind of unwinding those coils
okay now we've really separated this we've stabilized it and we're ready to begin elongating the dna
okay here's what's really interesting there's an enzyme that comes into play here
and it does something really cool it's called primase so an enzyme called primase will come into play here so what
zach you just said that we're making dna why the heck would i make rna there's a reason why
there's an enzyme that we'll talk about a little bit later called dna polymerase 3 that will
make dna but the only way it can do that is if it has some type of primer or three prime ohn to build off of so
in a little bit in a second okay so primase comes in so imagine here i just have like this cute little enzyme
here called primase okay and this cute enzyme comes in here and let's say here what's this strand up
here this top part remember we're going to say that this is three prime end where the o h would be
this is the five prime end where the phosphate would be and again the opposite strand here would
have to be antiparallel so five prime end here three prime end here right we already know that
the primase is gonna come in and it's gonna read the nucleotides and it has to go in a particular fashion
it reads it from the three all the way to the five end so what does it do the first thing it
what did i tell you that's super important what does dna replication occur even though this isn't dna
it's the same concept it synthesizes rna primers or nucleotides in a five to three fashion so it's going to
take and make a couple nucleotides generally it's about 10 nucleotides we're only going to draw a couple here
but it'll have has to be again five primes starting here and i'm just going to make a couple i'll
make like four nucleotides here okay so here it's going to have five all the way to the three prime end here
okay that's my five prime end here that i just started with and i'm synthesizing it in
the three direction now the reason why this is important is on that three end what do we have here
is another enzyme called dna polymerase type 3 comes in so there's an enzyme called dna
polymerase type 3 and he comes in and he needs that three prime oh from the rna primers in order
for it to continue to build nucleotides so again a big thing i need you to remember is it needs
the three prime o h of rna primer in order to carry out its activity if it doesn't have it it can't
and it says okay i have my three primo h region perfect now what i'm going to do is i'm going to
read my dna and i'm going to do it the same way that the primase did i'm going to read the dna from the three
once i read and figure out what kind of nucleotide is then i'm just going to synthesize
let's make a different color since it's a different enzyme we kind of picked red over there so
we're going to start off and we're going to say okay i'm going to take that oh and i'm going
to add a phosphate group onto it of a of another nucleotide so when i do that i'm going to continue to
fork again when i do that i read it i say okay let's say that this is adenine i'll put a thymine
this is guanine i'll put a cytosine this is cytosine i'll put a guanine and so on and so forth and i'll just
needed this three prime end of that oh of the rna primer to build off of it now here's what's really interesting the
there's just one rna primer and then dna the rest of the way this strand is very important we give it
a particular name the strand that's very continuous where the dna polymerase moves towards the
this other string which we're going to talk about is called the lagging strand something different happens where you're
still going to have the are the primase it'll come to this area okay on this other strand and again
it'll read it from three to five and then synthesize a couple nucleotides from five to three so this is the three
end it's going to synthesize from five to three and again the same thing will happen we created
three can build off of so now the dna polymerase type 3 will just pop on and say oh perfect i have my
now something interesting happens where it's gonna look it looks perfectly the same you're like zach i don't get the
okay so now let's come down here so let's say let's pretend right that for a second here we have
that primer let's kind of continue off this let's say that the helicase unwound the dna a
longer length of nucleotides so again let's say that here we had that primase came in here read this from one end
again this would be your three prime end this would be your five prime end so it'll read from three to
prime oh end the dna polymerase 3 says okay perfect i have everything i need i can continue
to grow and let's say that it just came up to like this point here but then you kind of unwind the dna
reading the dna from three to five and continuously synthesizing nucleotides from five to three so again this would
be your five prime end this would be a three prime end on this other chain this is on the leading
let's say that we continue to move on here and let's say that like at this point here this was where the
previous rna primer was from above where it had again reading this portion of the dna this is the five prime end of
from five to three and then what do we say happen from that part above we have the dna polymerase three use
from five to three here's what happens the primase lay down a primer here but the dna polymerase
iii has to use that primer to continue to keep building off if you unwind the dna a little bit more
so now here i have a couple more nucleotides now that primase after it just made down this primer for
the dna polymerase three to use it comes down to the next part of the replication fork and it says okay here i
dna polymerase says okay cool i got my three prime oh end here let me go ahead and use that to make
my dna and i'm going to read the dna from three to five and synthesize it from five to three
do you notice something really interesting here on this strand which we called again what did we call this
replication fork we called this the leading strand so the big thing i want you to know is that you
on this strand called the lagging strand something different happens here where you have a couple rna primers
okay and then kind of stretches of dna between those rna primers this kind of like broken up portion
where there's rna dna rna dna and if we continue to keep elongating it we'd have more rna dna rna
oka zaki fragments okay okazaki fragments and again it's basically where you have multiple
and then multiple rna primers it's a mix of them and that's a problem okay because you're
going to see now there has to be another thing that we have to do we want everything when we replicate dna
it has to be all dna we can't have it be dna with a little bit of rna so we're only using these primers as just kind of
a point to build off of after we've built some stuff we're just going to go in and cut those
things out because we don't really need them anymore so now let's talk about the next part
the next thing that you guys need to understand is okay we've used our rna primers for the dna polymerase 3 to kind
of build off of and make dna from we don't need those primers anymore we got to get rid of
them so let's draw the diagram that we had previously which again we only had what a little
stretch of rna primer here and then the rest of the length down going towards the replication fork which
so now this is really important we're going to talk about one more thing in just a second and again if you guys
so before we talk about how we remove these rna primers i really want to take a quick second here
to explain something else that dna polymerase type 3 can do so we know that it reads the dna okay
from three to five and then synthesizes nucleotides off of the rna primer from five to three
but it also has one other function it's called a proofreading function which is very important before we talk about the
mistakes and what it does is let's say okay it reads three to five reads all the nucleotides from a three
to five direction and then synthesizes nucleotides in a five to three after it does that it says okay
let me check my work it goes back and it finds the connection between this point says okay is this a
good connection yeah that's a good one a and t are connected together oh g and c are connected together a and
i need to cut that out so it reads from three to five and if it finds any mistakes it uses what's called a
i'm gonna read it and i says okay three to five i'm reading a t and again it's complementary base it
make sure i have it okay it was g that has to be c and synthesize the correct nucleotide in the five to three
reads dna three to five synthesizes nucleotides five to three proof reads back in three to five and if
and put in the correct complementary nucleotide very important okay now we got to get rid of these rna
is called dna polymerase type 1. so dna polymerase type one comes to the rescue and what it does is
it starts here and it finds this okay so let's say here we had our three prime end here
five prime end here the new strand would be synthesized from five to three what this enzyme will do is
it'll come in and it'll cut out these primers going from the five to three direction
the rna primers so this guy will come in and it'll say okay pluck remove that one pluck remove that
let's say okay it plucked off the rna primer reads it as adenine puts a thymine reads it as guanine
accidentally puts an adenine has to go back and proof read it though because that's always the thing that
i don't want that what do i need to do i need to pluck that thing out of there and put the correct nucleotide
finds an incorrect base pair connection it cuts it out and when it cuts it out it cuts that at a three
to five exonuclease type of fashion okay so the big difference that if you ever get asked between
what in the heck is the difference between dna polymerase type one and dna polymerase type three really the
it's just it has that five to three prime exit nucleus activity where it plucks out the rna primers
everything else is the same though now the next thing is dna polymerase type one we talked about on the on this
leading strand on the lacking strain it's a little interesting it'll come in and again it'll use its
five to three prime exonuclease activity so again let's use our combination here of what we know
this was three this was five so antiparallel this has to be five to three for the old strand the new
strand would then be what read three to five synthesize 5 to 3. so this dna polymerase will come
in and it'll start moving down and at this point it'll pluck off an rna primer and then what will it do
oh it is okay if it's not use my three to five primax nucleus to cut it out and then put in a new one it goes to the
next one plucks off the rna primer and does the same thing reads three to five synthesizes five to three proof
reads three to five then it just keeps doing that and plucking these things off here's the
difference though in the lagging strand it creates like a couple gaps these actually don't
completely kind of fuse together so let's kind of draw where we had this here and we'll create a little
space between these points here where the rna primers were so there's kind of a little space here
let's draw it here in orange so on the lagging strand it creates like a little space where it can't like
okay so it plucked the rna primers off and put nucleotides but it wasn't able to perfectly fuse these ends on the
those basically where those okazaki fragments were it'll come and it'll say okay here's
perfectly connected and continuous and now we have a parental dna with a new daughter dna strand again
a parental dna strand with a whole new daughter dna strand that is all continuous and all in sequence no rna
primers no nothing no breaks it's perfectly set now the last thing that i want to talk about
here before we go on to termination is we've elongated our dna we now took the old parental dna and made new dna
the reason why i want you to remember this is that there's it's very important for us emilies to connect foundational
sciences with clinical significance and so in people who have hiv okay their t cells okay their t cells
have are infected with the particular virus called a retrovirus and it's causing this virus to get
incorporated into the dna and then from every point that on that these t cells replicate they continue to
replicate more of the hiv genome so there's drugs that we use to target this hiv virus and particularly the t
inhibitors you're like holy crap what the heck does that mean i just want you to remember that they're drugs that
are used for hiv and they inhibit the replication process and t cells that have been affected with
hiv let me explain how this works this is really cool let's say here i just i quickly put down
an rna primer okay and i have my dna polymerase three it comes in here and it starts making
i give them a drug let's kind of put here an nrti and again there's many different names
of these like didenosine zydovidine there's a whole bunch of these but what i want you to remember is
what they do is is they remove the three prime oh region so now the dna polymerase 3 will get another
nucleotide it'll read this and say okay this is adenine i'm going to put a thymine or
something like that and i'm going to add in this drug this drug kind of floats around kind of
another nucleotide just like the ones i've been adding let me add this one on the only problem is is it doesn't have a
is inhibited are you able to replicate all the dna within these t cells that have been affected with hiv
no so that's how it does it they're what's called kind of like analogs nucleoside analogs
where you're kind of like dna polymerase 3 doesn't know the difference it's just taking nucleotides and adding on
and all of a sudden just by kind of chance you have this drug that it attaches on it doesn't know the
difference it goes to add another nucleotide on it's like hey that didn't add on what
the heck i can't add this nucleotide on and the dna never gets completely replicated so it's a good it's a good
clinical point to understand that covers our elongation let's hit it home with termination
and take a quick second to talk about telomeres all right this is actually the easiest one of all you're probably like
have another enzyme okay that helicase enzyme we're getting to the point where dna replication has been completed
we got that enzyme what was that enzyme that was working at these replication forks and just continuing to unwind the
and then you had those enzymes the dna polymerases type 3 and type 1 and all those guys that were coming and
basically reading the dna three to five and synthesizing it five to three proof reading in the three to five all that
meeting each other at kind of replication forks that are about to abut one another when this happens
when the gila cases meet and you kind of unwind this portion of the dna what's going to happen the helicases are
just going to kind of say oh well hey buddy i guess i don't need to keep unwinding anymore
and what will happen is you're just going to kind of have this point here where the dna polymerase is will just
and so usually once it gets to that point they'll just say hey i guess the helicases are done there's
no more unwinding for me and then after that the dna polymerases will say hey i've already kind of
so that's important so it's basically again where there's multiple origins of replication and they're constantly
moving towards one another whenever they moved and hit one another the dna replication at that point stops
now there's something else that you have to remember though dna replication will you know start at a
point and then work bi-directionally it's eventually going to go to the ends of the dna or the chromosomes which we
polymerases have a really hard time being able to replicate and that's very important we'll talk
about that next okay but again termination of dna replication it's really simple it's when the dna
stopped at that point they hop off and they no longer perform their function there's one other part of
it which is with the telomeres which we're going to finish off with all right so the next thing that we're
interesting issue that happens at the telomeres so one thing i need you guys to know is that
telomeres they really shorten over time so let's say that here we look at some chromosomes which again
made up of dna and proteins well let's primarily think of it as dna and let's say that this goes through
goes through a replication cycle a couple times i want you to notice what happens to the ends right so when you
the point in the center right which is called your centromere and then the ends okay these points here
and these are called your telomeres now what happens is over time as your cells continue to keep replicating the
and shorter as that continues to happen there's a worry with this and let me explain what that worry is
to proteins what are those called they're called genes so let's say that i have a gene right here
the telomeres will be there and their primary function is that they will it's common for them
this to happen where the telomeres were short and short and shortened but the whole purpose of
so do not code for rna in other words you can't take the dna from a telomere make rna make
protein that's important but let's say here there is a gene there that can make rna
the telomeres will kind of sacrifice themselves because dna replication doesn't occur at
this point for a particular reason we'll explain why and so because of that they prevent
gene loss so they kind of like take the hit for us if you think about it they're like don't worry i don't code
for any rna so you don't have to continue to replicate me so with each replication cycle the
reason because they do not code for rna and they help to prevent gene loss but here's the problem eventually you're
with the genes once that happens where the cell has reached the replication limit where it can't replicate
anymore it's reached its maximum number there's a particular term that you guys need to know and it's
called the hayflick limit it's called the hay flick limit and that is basically the maximum
let's say here we take and let's say that we use this as our example this is our leading strand and this is
we're going to use our rna primer here and then from here the rna primer was made by the what
enzyme primase dna polymerase type 3 will then add on to that 3-prime end and start making dna continuously
all the way down the leading stream remember it was continuous so this will happen all the way down
will have to add on to that three prime n so let's say it adds on right here at this three prime end when
it does that it gives a little primer and then again dna will build built off of that here's
another primer and then dna would be built off of that right so we kind of know that process
but here's what's different here watch what happens you guys your minds are about to get blown
remember dna polymerase one what does he come in and do comes and plucks off the rna primer
and then makes dna right on the leading strand on the lagging strand it'll come off and pluck this
portion here okay that rna primer and when it plucks off the rna primer it still has a what
n that it can use to build off of and make dna at this point here but watch what happens down here comes
down to this end here plucks off these rna primers uh oh do i have a three prime end that i
end i have no three prime end here that that dna polymerase can add on nucleotides to so dna replication
this was the old dna strand you replicated and made a new dna strand this one's going to get shorter it's
shorter than the original one guess what happens when this one replicates it'll get the new strain will
so thank goodness in particular cells where we have a need a lot of replication to occur we
for you so that way whenever dna replication does occur you don't start really taking away too
much of the telomeres and involving these really important genes so what is the name of this special
kind of ribonucleoprotein one arm comes here okay so remember we're just looking at this portion here
so we're only zooming in on this lagging strand about right here okay and zooming in on it
so here we're on this portion where we didn't finish and synthesize the nucleotides because again we didn't have
that three prime oh region here to add nucleotides off of the dna polymerase so what the telomerase does is it takes one
really cool it expresses nucleotides and a particular type of nucleotides that you guys really need to know okay
and the easiest way there's a mnemonic to remember them telomeres always have a particular repeat of nucleotides on them
on their three prime end and the easy way you can remember that repeat is the mnemonic tell them all
all the complementary rna nucleotides to this sequence that's commonly seen here so let's kind of write down what
template to make dna that's complementary to it so if it does that it's going to take
i elongated my three prime n okay which is important i elongated it so that way next time this dna replicates i won't
and says oh okay this is a i'm going to make t on the parental strand that's a i'm
going to make t on the parental strand so it can take rna and make dna elongating the telomeres
why would we want to elongate the telomeres we obviously know to prevent gene loss and so we don't
shorten those telomeres significantly and what cells would you want there to be a lot of telomerase
enzymes are a lot high activity highly replicating cells cells that are replicating so much that
those telomeres would shorten if we didn't have it so this is important you need lots of
you're like if you're a zygote and you're starting with one cell you need those
cells to have lots of telomerase activity to replicate and make the whole human body or your
hema hematopoietic stem cells which are making red blood cells white blood cells all those different things you need
those to be able to replicate and have enough telomerase enzymes so that it can replicate without hitting and losing
figure out a way to evade uh the cell replication where they can just continue to keep replicating
cancer neoplasia so cancer cells you know what they can do that we believe that they can do is they
upregulate the activity of their telomerase enzymes and if they up regulate the activity of their
telomerase enzymes they continue to elongate the ends of the dna on the chromosomes which allows for them
to continue to keep replicating and replicating and replicating without shortening the telomeres enough
really big thing i need you guys to take away telomeres shorten with every dna replication we
can prevent that with telomerase enzymes which perform what kind of process here reverse transcription use one arm which
and what types of cells normally would you see lots of telomerase activity normal stem cells highly replicating
all right ninja nerds that covers everything for dna replication all right ninja nerds so in this video
we talk about dna replication i hope it made sense and i hope that you guys did enjoy it alright engineers as always