in this video we'll be talking about cycling and cdk and their role in cell cycle regulation this is a slightly longer video please stay tuned till the end it would be highly beneficial and high yielded so what are cyclines cyclines are proteins that undergo cyclical pattern of synthesis and degradation hence they are known as cyclines so in certain stage of the cell cycle they are produced and in certain stage of the cell cycle they are degraded so they appearance or their activity is restricted in a Time bound fashion and this is how they are named as cycling because their levels rise and fall in a coordinated manner with the progression of the cell cycle and what are cdk cdk are cycline dependent kyes so they are obviously kyes molecules which are capable of phosphila but they are highly dependent on their partner which is cycline it's like they are a couple so without cycling cdk cannot perform any work so that is why they are highly dependent on each other so cyclan cdk act together as a unit this is the take-home message anyway there are important functions which are regulated by cdks at a structural level they are serenon KES so basically they're going to phosphorate serin oronine residues in the Target protein their activity is dependent on binding to the cyclines so without the cycl they are nothing C regulate the cell progression by phosphila several Target proteins that modulate events of the cell cycle and ultimately the activity of the cycline cdk complex is tightly regulated by several kinases and phosphatase action so let's look at the cyclan cdk which are active in different stages of the cell cycle in the G1 phase the most active cycling is cycan D and cdk46 complex in S phase cyclan e and cdk2 complexes are active at the end of S phase cyclan a and cdk2 complexes are active and in the M phase the key cycling that takes important role is cyclan B cdk1 in this video we would try to elaborate on each of these cycling and their activity so most important cycline is cyclan d cyclan e and cyclan B in a moment it will be clear so let's talk about the G1 cyclan or cdk complex which is known as cyclan D cdk46 complex let's see what this complex is capable of doing so cyclan D and cdk6 complex is getting activated with when there are ample amount of growth factor signaling now cyclan D is directly produced in response to mitogenic signaling or growth factor signaling so it kind of tells the cell whether growth factor is present in the environment or not if it is present in the environment then cyclin D would be produced The Complex would be active for example we know that mapin is pathway is triggered by growth factor binding so obviously one of the key Downstream Gene that gets activated in the RAS RAF Arc pathway is the cyclan D it is one of the most abundant Target Gene in this pathway so cyclan D is produced uh Downstream to the growth factor signaling and now it's important to note that whether to divide or not to divide is a very critical decision that cell has to make because it is totally energy dependent processes like DNA replication happening in SASE chromosome segregation happening in the mhase all of these things requires a hell lot of energy so if nutrients are not present then it is not a appropriate time to divide so there is a particular point in the cell cycle known as restriction point where cycline D cdk4 take critical decision they took took all the information from growth factor signaling nutrient availability and stress factor based on all of these they decide whether cell should cross restriction point or they should not cross if restriction point is crossed then it has to divide so there is no point to back out anyway that is why cyclan D cdk4 activity is really important now I'll tell you that how prb which is particularly a tumor supressor protein act to modulate the cycline D cdk4 activity or Cy and how basically prb regulate the cell cycle progression so basically it's a tumor suppressor protein it would suppress the growth it is produced by rb1 Gene which produce the rb1 MRNA and translates into prb protein now prb protein acts in the Restriction point now it's important to note that how prb works so prb is a critical decision decision maker prb can actually inhibit a compound known as e2f e2f is really important for cell cycle progression to S phase because e2f can selectively bind to the DNA and e2f can help to produce the um SASE cycling but e2f is only able to do that when prb let it be separated right so when prb is separated from the e2f complex e2f can do its job so that is why separating e2f is really important now here is cycling e production that happens when e2f binds to the DNA cyclan e mRNA is produced and cyclan E is produced and this is really important for replication progression but here is our inhibitor prb because prb sequesters the e2f and don't let it bind to the DNA so who would tell prb to back off and this critical job is done by cycling D and cdk 4 if the environment is favorable growth factor is present cell has enough nutrient then cycl D and cdk4 would phosphorate prb and phosphila prb allow it to be removed from the e2f complex so it is De inhibiting the e2f complex and basically e2f complex is now free to bind to the DNA and allow the cell cycle to progress from G1 to the S phase this is how cycan D and cdk uh 4 as well as cyclan eproduction is really important in this G G1 and S boundary so now we understand its highlight okay now there is another protein another tumor suppressor which can modulate cycline CD can thereby regulate cell cycle this is p53 It's a tumor suppressor protein it plays key role in cell cycle regulation apoptosis and maintenance of the genomic stability it can actually pause the cell cycle progression in many ways but why P 53 should pause cell cycle why it is important and what is the consequence so let's see let's say there is a DNA damage that happened during let's say G1 phase now if this particular DNA damage is not repaired there could be detrimental consequences because these are really delorious in terms of uh nature so basically there could be blockage of the replication fork there could be loss of a chromosome segment and the worst outcome is basically apoptosis or death of the cell now p-53 can modulate the cycling and prevent and pause the cell cycle how it is happening so basically there are specific sensors known as ATM ATR which can bind to the DNA damage sense the DNA damage and with Downstream signaling Pathways like which involves check 2 p-53 can get activated now normally p53 is degraded but when check to phosphor at p53 it is activated and p-53 can do many things it can activate p21 which is a negative influencer of cyclan cdk activity now when p21 blocks the cycl cdk activity cell cycle is paused cell cycle cannot progress further now you must be thinking why it is good sometimes pausing the cell cycle is important because once the cell cycle is paused it would give DNA repair Machinery enough time to repair this damage there are homologous recombination mechanism there are non-homologous enjoining mechanism by which DNA can be repaired for argument sake imagine the DNA is repaired then cell cycle is resumed and the pause is done and thereby the cell cycle progression happens and cell divides now imagine the cell cycle progression is paused but the damage was beyond repair it cannot be repaired in that case cell would be uh induced for apoptosis so p53 actually coordinate with caspas 3 and basically Target the intrinsic pathway of apoptosis it activates back and bad which pokes whole in the mitochondrial membrane basically cytochrome C leaks out ultimately caspace 3 is activated which triggers the apoptosis response now we understand how p53 modulates cycline and thereby modulating uh basically the cell cycle so basically one outcome was the damage was repaired cell survives and go to the cell cycle another extreme outcome was cell would die because the damage was irreversible and instead of of segregating faulty chromosome it was good to kill the cell because if this is not prevented it might lead to tumor formation or sort of cancer formation and indeed many p53 mutations are associated with cancer then we move into s-phase cyclines sface cycl is cyclan e and cdk2 is the corresponding cdk partner so in this case let's see how sface cycl helps in the replication initiation process so in at the end of G1 the replicator sequence is is already bound to the origin of replication complex it also binds to ctd1 and cdc6 it loads the MCM 27 helices so these helic would form the replication bubble but that requires a licensing event that licensing event is happening with the help of kinases cycling dependent kinases so there are two events replications replicator selection and there is another event which is origin activation this origin activation is the license ing event that has to happen but who gives the license in S phase the cyclan E and cdk2 activity is high so this particular complex can actually phosphorate these ctd1 cdc6 and thereby allow the replication bubble to form so it's important to note that this replication bubble forms at the beginning of the S phase and in any other stage since these particular components cdt1 cdc6 all of them are hyper phosphor dilated then what happens is they cannot get reassembled into the replication complex thereby it also ensures that replication only happens once in the cell cycle so this is a big achievement of the cycling cdk complex it ensures that replication happens only once in eukaryotic cell cycle and it never happens twice and this is the mechanism anyway you can watch the detailed video video on eukariotic replication to know it better anyway it's important to note that in this replication initiation as well cycline e cdk2 complex has huge contribution then we talk about the mphase cycline which is cyclan B cdk1 cyclan B cdk1 has different phosphorilation sites such as tronin 14 3in 15 are inhibitory sites 3in 161 is activatory site several kinases like V1 kyes inhibitor perform inhibition with the help of phosphorilation there are also activat KES such as cines there are also activatory phosphatases which remove this phos inhibitory phosphorilation and allow this particular cycl 2 gets activated anyway when cyclan B and cdk1 complex is activated it can lead to many biological function like chromosome condensation nuclear envelope back breakdown fragmentation of Golgi spindle appar spindle apparatus formation Etc anyway after its job is done it would be degraded with the help of polyubiquitination by anaphes promoting complex when poly uation marks are added onto the cycline B they are destined to be degraded by proteosome mediated degradation anyway cyclan B and cdk1 are really important kyes because in the beginning of the prophase cyclan B cdk1 phosphates the lamins which are the intermediate filaments supporting the nuclear envelope so it leads to breakdown of the nuclear envelope so once the nuclear envelope is broken down the nucleus gets basically uh separated and the chromosomes get slowly condensed so lamin dissociation is a important event performed by cyclan B cdk1 second thing is it can phosphorate condensins condensins a structural maintenance of chromosome proteins which basically condense the chromosome this is how cyclan B cdk1 complex plays vital role in packaging and uh condensing the chromosome at the onset of the m phase I hope this video was useful we talked about the G1 the S and the mphase cycling how they work and how they regulated get more notes and flash card in our Instagram and Facebook page you can support our video with uh super thanks you can pay via PTM PayPal or UPI see you in next video