How DNA unties its own knots - Numberphile
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- เผยแพร่เมื่อ 1 พ.ย. 2015
- How "Pac-Man" unties knots in our DNA... This is Part Two of DNA Topology featuring Professor Mariel Vazquez from UC Davis.
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Part One: • The Shape of DNA - Num...
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ADDITIONS/CORRECTIONS:
0:14: In addition to Sumners and Diao, Whittington was a key contributor.
2:26: "flouroquinolones" should read "fluoroquinolones - วิทยาศาสตร์และเทคโนโลยี
being a bio student it feels great to actually understand something for once in these numberphile videos lol
+blublopble Could this be the beginning of "Biophile"?
+blublopble Being a math fan it feels great to actually learn something I find interesting about biology :P
(No disrespect, it's just not my thing)
Lol I know how you feel! Finally I don't feel dumb for not understanding the math stuff
MrFreakHeavy
Nicely summarised!
+Marcio Zygmunt
The double helix unwinds at a point called the origin. The bonds between the nucleotide base-pairs are then broken, leaving you with two single strands of exposed DNA at the origin.
Nucleotides floating around then attach onto both exposed single strands, in a complementary fashion (A-T and C-G). The unwinding continues down the double helix DNA from the origin, and more floating nucleotides (AKA free nucleotides) attach on where the DNA is exposed by unwinding + base-pair bond breaking.
The result is 2x double strand DNA.
It's almost scary how this micro biology stuff works.
+luckystrke My trouble with biology is that I always end up feeling like I haven't learnt "how stuff works". Just saying within cells there are "Type II Topoisomerases"" (A word I'm never going to remember), go around the cell and break the DNA in places that are knotted and re-attach leaves me pretty unfulfilled.
I'm just left with no clue these enzymes:
1. Locate knots, it's not as if they are conscious pac-men with the ability to say "Hey, there's a knot over here I better go over and fix that" or "Oh there are more knots, no problem! I'll go fix those".
2. Break the DNA molecule once they have located a knot
3. Avoid breaking DNA in places they don't need to, or if they just do anyway
4. Assure that the DNA is reattached correctly
etc.
Whereas with mathematics I can always leave happy since if there are any theorems used in a proof that I've never seen before I can either: try to prove / work out why they are true myself, or read proofs online.
+Bradley I share your feelings. In bio sciences, you almost never get the actual answer. It's all far too complicated, and sometimes it doesn't make sense at first sight. It feels like, no matter how deep you get involved, you only get a tiny fraction of the cake.
You can ask any professional something about their field, and there's will always be an "I don't know", "we don't know yet". But because it's so deep, it's also pretty fascinating. :)
+Bradley oh, and partial answers to your questions: it's pretty much driven by bioenergetics.
The enzymes locate knots because they are made to fit into them. Therefore, if there's a knot and an topoisomerase is near, the most favorable reaction will be the topoisomerase approaching the knot and, for the next point (2.), break the hydrogen bonds. This breakage is a pretty standard reaction that is actually driven by a lot DNA enzymes (but with other purposes).
Also, the name "topoisomerases" comes from the fact it modifies the "topography" of DNA, without altering its molecular formula (iso means same). I never remember the type II part so don't bother too much about it.
How do they avoid breaking DNA in places they don't need? It's wouldn't be a favorable reaction so it's unlikely to happen, however I won't tell you it's impossible. Errors in DNA occur all the time, there's also plenty enzymes to solve that kind of things.
And finally, how it's assured? The enzyme is build to go through the complete process. It's not like it first breaks and then re-bond DNA. Let's say the enzyme binds a knot: it whether breaks it and reattaches it or it doesn't do anything. It will never break and stay as that, because that's an unstable process.
Hope that was helpful, even though I know there's still a lot of things to ask in the air. In case of any mistake, I hope someone points it out. Have a nice day.
+Bradley Biochemistry is a very daunting hunk of academia to approach. Math is the basis of chemistry, chemistry is the basis of biology, so we are dealing with a higher order of scientific understanding. The chemistry underlying enzymology and the many interactions that occur within a cell are so complex that trying to explain any part entirely would require educating the population on basic and advanced chemistry.
If you had the knowledge necessary, you could double-check the experiments, or at least double-check the theory's plausibility in terms of enzyme reactive sites and DNA topology, etc., but chemistry will never be as clear cut as mathematics.
+mygoldentruth Wonderful response!
Brady, will you make a video about headphones knots?
Yes please!
+dominikstepien2000 What do you mean - knot theory? Objectivity?^^
+Arnim Sommer Subjectivity FTW
+dominikstepien2000 It's easy to explain though, it's simply because there is only 1 state of not knotted, yet many for knotted, so it's sure to knot
+Prich038 To add to that. The longer the strand, the more states of knotted you add. The more ends to the strand, even more states of knotted.
To exemplify in a oversimple manner. If a knot requires 1 inch of strand to exist and the strand is 2 inches long with 2 ends. We have 2 to the power of 2 possible knot states. If it has 3 ends, 3 to the power of 2 knot states. This ignores the analog nature of knots and assumes they are digital (a knot could only appear in a given spot) but in reality that's not the case so these numbers are even further blown up when you account for the analog nature of knots.
In Norwegian we have a figure we like to call Kabelsatan. He is essentially a spoof of the popular kids' show pirate Kaptein Sabeltann (Captain Sabretooth). Kabelsatan literally means Cable Satan, and his soul purpose in life is to torment people who have any affiliation with cables or wires of any sort. Do you often find your headphone chords in a tangled mess of knots? That's the work of Kabelsatan. I guess he has some issues with DNA as well xD
+Ze Rubenator lol I learned a small portion of norwegian culture
+Ze Rubenator
I'm German and I totally get you for we have a similar word in German: Kabelsalat :D
+Ze Rubenator And also, Norwegian fishermen will stock their rope, on deck, in an 8 figure shape. In order to avoid the mess.
+Ze Rubenator In our country, his name is Comcast.
+Gummans Gubbe There is a way to wind rope (or garden hose) on one's forearm that avoids it becoming progressively twistier. I bet that's what is going on that produces that that figure-8 shape.
Oh man I hope there's a pt. 3
+Slpk If there were, it'd probably be linked at the end of the video. Alas, it is knot.
+sk8rdman ahhh, I enjoyed that
JamesTCope225 Enjoyed what?
+sk8rdman The comment's gone. It was something funny, but I don't remember it anymore.
+sk8rdman oh wait, I remember. "It was not" like knot
Being a biology major and math minor, I especially love when Numberphile covers mathematical parts of biological processes. Thanks Brady!! :)
Fascinating.
this is fascinating man, i love seeing maths being used in places especially like biology and things where you might not expect it to come in handy
I like how Numberphile is a big youtube channel but still you'll exclusively find good questions and answers in the comments helping you to understand what you didn't in the video =)
PS : To you, yes you, this message is a statment, not a comment xD
+Furrane Me?
+Yan Wo Yes you
+Yan Wo Who ? You Wo Yan !
The applications of mathematics will never cease to impress me!
I absolutely loved this episode!!! I have always been fascinated by DNA structure. Thank you!
Lol, I've just read chapter in a book "Things to Make and Do in the Fourth Dimension" about knots, and now you explain it to me once more :D Love you, Numberphile :D
Excellent description and outline of the topology of DNA replication from Prof Vazquez. Leaves me wanting more, Brady ;-)
This is the best NumberPhile video I have seen in a loooooooong time. More number theory and especially more of this guy please!!
o.O But HOW does it know that the DNA needs disentanglement, and how does it know where to perform the break-and-restitch without actually *increasing* the entanglement?
+stellarfirefly from what i remember there is a code for start cut here it might be like GGGGAAAAGGGG so when the thing reads it and it knows where to start and there is one that tells it where it ends as well.
Kien Soyokaze
Ah cool, that explains how they know where to splice. But how do they know where and when to re-attach without actually increasing entanglement?
my guess is chemical based most likely hormone levels tell the DNA to start making more or less of
Let me clarify: How do they know *where* to re-attach? Immediate re-attachment will not change anything. The endpoints must be moved in space to a different location and then re-attached, but that location must not be somewhere that would make the new link even more entangled.
+stellarfirefly Echoing Zack, I imagine the enzyme's action is to physically grab two strands, then break one, transport it, and re-attach on the other side of the second strand.
I'm still confused as to how it knows which adjacent strands to break-and-restitch and how it knows when to stop. I suspect +doland trup 's answer below. Any individual reaction is not nearly so well coordinated; however, millions of these reactions will statistically be governed by energetic and entropic considerations.
I'd love it if someone wrote an article explaining it! (or a video, this is youtube, after all.)
4:23 complementary strands of DNA do not have the same genetic code. They have complementary code. Typically only one side will carry genetic information (though it is possible for each side to carry information, read in opposite directions).
+EebstertheGreat In the actual cell, complementary pieces are added to each half of the original strand at the same time that it is split.
JWQweqOPDH Yes, each strand has the information required to reproduce the entire double helix. However, that doesn't mean either strand could be transcribed to produce the same mRNA.
+EebstertheGreat The information caried is still the same tho.
***** I guess. The word "thing" and the numbers "20 8 9 14 7" carry the same information, but they don't mean the same thing.
EebstertheGreat Well, not really. AAGT and TTCA have the same information, as the difference between their units is the same, if you see what I mean. It's like 4 + 4 = 8 carries the same information as 8 - 4 = 4.
The flying spaghetti monster thought of everything. Ramen.
I need tiny pacmen for my headphone cables.
I really liked this video. Math and biology are two of my favorite studies. I hope there are more videos on this to come.
Oh Professor Vasquez, you are awesome. Great work! ❤❤
Science and nature here, is endlessly fascinating. Amazing stuff.
Fantastic, never thought about it!
1:34 There it is, written down: _Type II Topoisomerase_.
This is in case anyone else, like me, missed it the first time.
(The lady enunciates it _extremely_ rapidly throughout.)
little robots that you put in your pocket that untie things you put into your pocket/ keep them from becoming tangled.
Thank you for being my go to channel for getting my little brother to go away
My dad is a sound engineer, and has worked with cables his whole life. He taught me how to avoid knots on headphone cables. It's easy, really, it'a all in the coil. If you, when you wind it up around your fingers or whatever, do alternating overhand and underhand loops, then the probability of there being knots on the cord after a few hours in a pocket goes greatly down (I would say to around 1-5%, based on my own empirical evidence).
A VIDEO !!!
Opened this video, and after just two seconds I came to the realisation I'm not in the mood for Numberphile first thing in the morning.
@CaesarsSalad it does in eukaryotic cells. But prokaryotic cells have circular DNA as it is easier to keep it altogether than individual parts.
Thank you type 2 topoisomerase.
That is so cool! :D
I am so impressed with DNA
If I put some of these enzymes in my pocket, would my ear phones cable be safe?
This is really fascinating! But how exactly does the enzyme know when "it's done"? Are the things who pull on the DNA keeping stress on the DNA and as soon as the stress is released the enzyme considers it done?
Interesting...Thanks Much.....!
Great video, loved the Pac-Man reference :-)
This reminds me of Matt Parker's talk over on The Royal Institute youtube channel. 4-dimensional maths, I think his talk was called.
Thank god this isn't a podcast. I need pictures!
Did these enzymes evolve before DNA? It seems as though DNA is reliant on the enzymes so it seems like a chicken or the egg situation.
+Owen Prescott Which is why many biologists believe that life started out as RNA-only: no DNA, no proteins. But yeah, this kind of stuff kinda makes you appreciate why life had to remain in a very primitive form for billions of years before all the right machinery was in place to form all the complex body plans we see today in just a few million years and only half a billion years ago.
I'm just guessing, but I would guess something like that ancient cells only had very short dna strands, so didn't get tangled up so much, and that these enzymes evolved as dna got longer and longer. Although even short dna loops would need these during reproduction. Hmm. Perhaps they came before dna, I.e. from some RNA life.
ninjafruitchilled Exactly, it's fascinating to think that no prokaryote would ever divide without this enzyme in place.
+Owen Prescott Penny lane is correct: scientist are now more inclined to beleive that an RNA world happened before the protein-DNA world. The evidence is that some RNA starnds have been reported to have enzymatic properties and can even catalize their own replication. Put that with the fact that RNA can also store information and you get a molecule that acts like DNA and Proteins.
Thanks for the awnsers, if life can indeed function without these enzymes then it makes more sense.
Hey!
Could you make a video of "Power of two". 2^n.
Thanks!
I have no idea what you lot are talking about but refreshing not to see any put downs or vile comments. I love Numberphile - thanks for your interesting comments!
Wow. Just... wow.
Love the link to biology!
--Computational Biologist
It's amazing how those little enzymes know more about topology than me. But how do they know where to cut, what mechanism do they use to detect a genuine knot?
This means that topoisomerase is able to distinguish a knot or a tangle from overlapping strands that are not knotted (otherwise it could just as easily be inducing knots rather than removing them!) Is there any knowledge as to how that is done?
Interesting it is.
Will the drug affect the type-2 topoisomerase in the host's cells as well?
Thanks for the video. In my job i deal with microbes and DNA, but i didnt knew that ther was topoisomerase.
even learning somthing about dna on youtube, didnt expected that..
How does the enzyme detect DNA knots? I assume it doesn't have eyes. Does it feel them out somehow? What if several of those enzymes are repairing knots (I assume there must be more than one working, for it's a long chain), how do they know to work together? How do they know when they are done?
God, remember the good ol' days when this used to be NUMBERphile, and NOT DNAphile!!!
For a human DNA that has two ends, you won't have interlinking post-DNA splitting, right? We don't have any topological problem, so do we need / have that 'Type-2-Topoisomerase' ?
Damn it y'all making me excited for my math degree programme
WTF did I just learned? that just blew my mind...We play gene warfare on bacterium by letting them knot up... I knew I subbed this channel for a reason.
Is DNA always an even helix? If not, how does this work on Mobius strips?
I wish i had this vid when i was learning Biochemistry
At 4:55 or so, it is stated that there need to be 2 cuts to separate the strands. Why is that? If they re just linked circles, why would you need more than one cut and sew to separate them?
What's the name of the theorem she referenced in the beginning?
@anisometropie Benihime probably due to electron density leading to a charge imbalance. This leads to a change in the protein's 3d structure and that lead to activity or anergy.
How fast does this untying occur?
When making her model circular genome Professor Vazquez says she has to give the ribbon an even number of twists to avoid a Mobius strip. This classically has just 1 twist and will not cut along its length into two interlinked loops - only an even number of twists (2 or more) will result in that, as far as I've personally checked anyway. In reality even the circular helical genome of a bacterium must have at least thousands of twists. Is it a matter of chance whether that number is odd or even? And if odd, replication will not result in interlinked loops, just one continuous strand, right? So what does the topoisomerase do then?
there are lefthanded people so are there any left handed dna?
Does our topoisomerase diffrent from bacterial topoisomerase?
i love hearing complex words from foreign tongues
One simple question, how the DNA perceive that it's tangled and not simply folded?
I want more about Knots and DNA
man we need just really small cameras so we can see how it really works...
I am interested in the names of the mathematicians authors of the theorem that says that given a sufficiently long cord, in a confined environment, it will knot with probability 1, in the audio I could not grasp them correctly; please!
Hi Arturo, I didn't see your comment sooner. The statement is known as the Frisch-Wasserman-Delbruck conjecture. The first mathematicians to prove a version of it were Whittington and Sumners, and independently Pippenger. I hope this helps!
Where's the paper on the theorem she mentioned in 0:10?
Would some helpful biochemist please mutate some Type II Topoisomerases so they can unknot headphone leads?
Is the helix and knotting significant to the actual process of replicating
or is it only a matter of compaction that needs to be undone before the
replication can happen.
Not entirely sure here, but I'd say knotting is a topological side effect of a long strand of anything packed into a small volume. The helix results from the chemical composition of the DNA and how much energy certain molecular conformations have (chemical stability). I think neither is required for replication.
Uh-huh. Uh-huh. Yeah, I also exhibited spontaneous nodding while watching this video.
is this process in anyway related to dna mutation?
@JimAndNathanDoTheGames the thing is DNA would have been much shorter then and so they would have not need a unwrapped what it should have maybe needed is a way of recombination and that would need a restriction enzyme and a ligating enzyme.
@alex1902961 because of electron field density and stoichemistry
those little pac-mans are so adorable
talking about knots with a celtic knot necklaces. WIN>
Biophile?
4798alexander4798 CrashCourse has a playlist of 40 videos over biology. It's by the same dude who stars in SciShow (Hank Green I think). But Brady's video was more integrative (math, micro-biology, pharmacology, etc) and not animated.
Am I the only one here now imaging billions of tiny Pacmen running around my cells shouting out, "Am I done?"
I like how she calls the Gordian mess in my pocket "topological complexity" ;)
Hmm, this pointed out an interesting problem to for the circular DNA strands. The video specifically referred to a non-mobius loop; but what if it was rotated an uneven amount of times? The strip created by doing the division process represented by the scissors would yield a single band, and to correct this the loop would first need to be cut perfectly half-way down the length of the DNA, which I would expect is a much harder task to achieve than just breaking the intermediate H-bonds.
Without the presence of an enzyme capable of either cutting it in half by length or one capable of preventing non-even turns in the first place, it seems like any closed DNA bands would only have a 50% chance for successful replication.
Well, the only problem with that analogy I see is that when the DNA splits for replication, both halves undergo the same process of attaching floating base pairs to the existing half-DNA strand, making two new ones. If what you propose is true, I would expect it would require a *very* different mechanism of DNA replication than what has been discussed here. I honestly have little more than guesses too, but I would be interested to find out more :)
Voidfury under the "overview" section it says that each strand is like and arrow with head and tail. I think this answers the question but it would still be nice to have an expert pitch in.
Interesting, I wonder what physically orients the strands for the enzymes to know which way is which. Thanks for finding that info.
I think still more interesting (the brunt of my initial comment) is the case of mobius-esque circular DNA band that once the enzyme polymerase breaks the H-bonds into the two 'separate' sides of the helix (which are not actually separate if you follow along the length of either side) you have to deal with a single loop that is double the length. No amount of untangling would fix this, since the shape has fundamentally changed instead duplicating. I am really curious to learn of which mechanisms exist to handle this.
I really don't think that any mechanism of defining direction or orientation here would impact this process, since the problem is caused by a twist that exists regardless of direction along the loop.
Is anyone else's mind as blown as mine is that all of these "useless/just-for-fun" videos that we've been watching about the mathematics of knots and mobius strips suddenly got really real? I'm waiting for the biology of a klein bottle next. ;)
how does it break it and relink it on a molecular level?
+doland trup So it's just chance they find the knots and cause these reactions? Why does it only specifically work at a knot and nowhere else on the DNA?
+XxCLIqGamerxX I'm not an expert on topoisomerases, but from what I know about protein interactions, it's likely that there are other proteins involved in this process and that they were omitted for simplicity's sake. So, while the topo protein is doing the heavy lifting, it's likely not directly responsible for identification of the topological problem. Identification is probably the role of smaller, much simpler proteins which are 'designed' to bind to these regions thereby allowing them to recruit the topo protein and activate its unknotting ability. (Or, even more likely, binding to a series of proteins which, in the end, recruit the topoisomerase to the site). Essentially, there are molecules which act as a signal to say "hey, topo! over here!" and it comes a runnin'.
It's common for these sorts of large-scale cellular responses to involve many proteins of differing abilities all binding/interacting with one another for some singular effect, but it would be difficult to explain to the layman in a 6min video without making things needlessly confusing. Therefore, it's simplified to "topoisomerase does this" because it's the protein chiefly responsible for the phenomena being described, even though it's not the only one involved.
1:35
i didnt know ikea was among "possible organisms" DansGame
The pacmans are adorable
Does dna always loop back on itself? Are they free strands or are they all non-möbius circles?
+NonDelusional74611 In bacteria, chromosomes are circular as are plasmids. In the higher life forms, DNA is capped at the ends. The chromosomes have telomeres at their ends.
+NonDelusional74611 They always loop back on themselves in prokaryotic dna (bacteria) or free plasmids (loops of DNA that exist independently and enter into cells). Eukaryotic cells don't loop
+NonDelusional74611 The answer to that question is in the first video ;)
How do they bloody know what a topological complexity is ? it’s freaking enzymes ! how do they know how to do that ?
Effing enzymes! How do they work?
+anisometropie Benihime Enzymes are machines that catalyze reactions, not animals with minds that know things. They don't know anything. Seriously, no thought process at all! Same goes for cellular organelles, cells, plants, and fungi. Even most organisms which have nervous systems aren't capable of "thought" and don't possess "knowledge." They do what they do because natural selection has shaped them to do it automatically.
How do chloroplasts know how to photosynthesize? Have they studied biochemistry?
How do my blood cells know I need oxygen? Have they studied medicine?
How do termites know how to construct an expertly engineered fortress? Have they studied architecture?
+anisometropie Benihime they don't know how to do anything. they formed and happened to have the properties which make them perform their function, which allowed the cells that they formed in to reproduce.
+Eric Anderson We're just astonished that these little guys can solve topological problems by only acting locally using a small set of basic instructions.
+anisometropie Benihime molecules don't "know" any more than Jon Snow, you have to think about all of this as a clash of probabilities. Think about the sheer amount of these bumping into each other all the time and then how often the desired reaction happens.
Look! A knot! Knot anymore!
now i want to play pacman :D
lol the animations.
So there must have been a time where DNA length was limited by knotting and then the first DNA that could produce Type 2 topoisomerase had the evolutionary advantage and could more length and complexity to its self more than its competition could and therefor won out the evolutionary war
Are the knots now mathematical knots or "normal" knots like on your shoes
+Phil H.
i guess the shoes can be called "tied" not knotted
going technical
+Phil H. Considering it's made of molecules and not just information, it's a "normal" knot.
Thanks!!! For the fast answer
Quantum physics.
DNA is a molecule.
Therefore DNA is tangled and not tangled at the same time.
Biologiphile please please please
Put your finger in your ear and scrap it up and down... now you can hear your micro-Pacmen in your cells :D
I think technology is amazing but compared to life, our technology is still incredibly primitive and humbled by it.
How does this sorcery happen.
im early to comment! what is the probability that out of all numberphile subscribers, im the first to comment on new uploaded video?
+Izzat Zubir 1/1 413 674 chance. Althought that's excluding inactive subscribers. Most videos seem to have about 1/240 000 so that's more likely. Althought most likely too low of a chance. That's not even including the time factor of how many people watch it at one time, how many cares to comment and etc.
Lol, Little Pac Men
Tongue swollen?
I have a question what is really a topoisomerase? And what make them act, i guess they are also made up of molecules?
So how could they identify a knot, isn't that just weird? What is the difference between dna, proteines and topoisomerase?
+Jonas Thörnvall It seem a quite advanced problem to recognize a knot because there are false knots, and it seem unlikely that a strand of molecules are intelligent, so what is going on?
So it probably some simple math dependent upon chemistry chains that make it recognize the knot?
But is that enough to make something that i would call noneorganic to act?
When are a chain of morecules organic and what makes it organic?
+Jonas Thörnvall Is the math that make the replication explored and is there an algorithm to simulate it?
+Jonas Thörnvall Is an enzyme an organic molecule chain, if so what differ it from an inorganic?
+Jonas Thörnvall topoisomerase is a protein (its an enzyme). It has a binding affinity (an area of the enzyme is attracted) to the region where the crossing of DNA strands is. When it binds to that region, the binding itself changes the shape of the enzyme which allows for the next step to occur. You are best off googling the terms to understand the differences. As to "what makes them act"... its all just chemistry.
+Jonas Thörnvall I'm also wondering how they identify a knot. I don't know, but it seems impossible without looking at the whole two strands together.