in this video we'll be talking about cell cycle checkpoints and this video is quite detailed video so stay tuned till the end and you would get a total explanation about cell cycle checkpoints now there are three cell cycle checkpoints that we are going to talk about this operates in g1s transition G22 M transition and within the M phase the first checkpoint that we are going to talk about is g1s transition checkpoint also known as the Restriction point so in this particular restriction point or in this checkpoint cell assess its environment cell looks for growth factor growth conditions and understands whether it is optimal condition for dividing or not also it looks and monitors for the internal damages like DNA damage so obviously it's one of the most important checkpoint or the DNA damage checkpoint so imagine there is a DNA damage that has accumulated in G1 phase and in this phase if the DNA damage persist then the consequence is detrimental because there could be replication blockage and there could be faulty chromosome segregation eventually that is why there should be checkpoints which can possibly block the transition of the cell cycle and this would give the cell enough time to repair its damage that is why g1s checkpoint is really useful let's see how this checkpoint operates at the molecular level so the cell has to First sense the DNA damage then pause the cell cycle give the give give itself enough time to repair the damage and then again resume the cell cycle so one of the key thing that the cell has to do right now is to pause the cell cycle and that can happen in several ways but before that cell senses the DNA damage with specific DNA damage sensors like like ATM ATR Etc so all of these are kyes molecules so which can phosphorate Downstream Target such as cze 2 and cheze 1 kyes now cze 2 kyes actually phosphates p53 which is a tumor suppressor protein its inherent goal is to suppress the cell cycle anyway phosphorilated p-53 is free and it cannot be degraded generally under normal circumstances p-53 would be degraded and basically mdm2 degrades the p53 in ubiqutin proteosome mediated pathway but when there is a damage happening in the DNA p- 53's goal is to stay protected and then prevent further damage so p-53 would perform specific task p-53 activates p21 which is a cycl dependent kyes inhibitor so it would inhibit cyclan cdk complexes thereby pausing the cell cycle progression from G1 to S now let us quickly recap and resume so p-53 would pause the cell cycle give it enough time to repair the DNA for example via homologous recombination based repair the cell would try to basically repair the damage but imagine the damage is not repairable then what happens in that case the cell would choose the hard way of undergoing apoptosis it is better not to segregate a faulty chromosome than dying because once these M mutations accumulate in the genome it would increase the risk of tumor formation okay so now we understand what really happens in the DNA damage checkpoint in the g1s transition so basically just to summarize DNA damages are sensed by kyes which recruit p-53 p 53 further activates cycl dependent kyes Inhibitors and thereby cyclines are inhibited so cyclan D cdk4 complex which operate at G1 phase is inhibited and second cycline e cdk2 which is important for S phase transition is also blocked as a result the entry into the S phase is blocked so the cell cannot move from G1 to S phase so this is the goal of G1 s checkpoint so these are the summarized point for g1s checkpoint anyway prb which is another tumor suppressor protein plays critical role in this checkpoint as well I have a different video on prb click on the IE button to get that video now next we talk about the g2m check point as the name suggests it operates in the g2m transition point but what does it look for it looks for DNA damage Point number one and point number two it looks for unreplicated DNA so basically if the replication doesn't happened properly in the S phase and there is some sort of unreplicated DNA that can also be sensed using this checkpoint and even after replication there is some damage which requires or let's say there is some mutation DNA break that occur during the replication phase that can also be sensed using this checkpoint so let's see how this checkpoint operates at a molecular level so entry from G2 to M phase this particular uh transition requires the activity of cyclan B and cdk one this is the mitotic cycline now any DNA damage would anyway be sensed with molecular senses like ATM ATR that can activate Che 1 kyese which inhibits cdc25 now cdc25 is a crucial phosphatase that activates the cyclan B cdk1 cdk1 complex so obviously when cdc25 is inhibited with the help of Che one kyes then this activation step is abrogated one cycling B cdk1 is not activated the transition from G2 to M phase cannot happen moreover Che 1 kyes can also phosphorate p-53 which activates p21 and thereby the cyclan B cdk1 activity can actually be inhibited now this is really crucial because if there is DNA breakage or unreplicated DNA it's not wise to enter the mhase and condense the chromosome because again we know when the separ would happen there could be a faulty separation that is detrimental for the cell that is why pausing the cell again recruiting the repair Machinery at this point is again important then we talk about the mhase checkpoint which obviously operates in the mhase more precisely in the metaphase and the anaphase transition now the cell ensures at this point that chromosomes are properly aligned in the spindle fibers because before the divis division or segregation of the chromosome this alignment is important proper tension has to be sensed at this point otherwise segregation would be unequal so this checkpoint helps to prevent any errors in chromosome distribution in the daughter cells so what happens in the anaphase is chromosome segregation and this is a tightly regulated process because a defective segregation might lead to detrimental consequences now in the L metaphys what happens is there are anaphase promoting complex which generally inhibits securin and basically separase is now free so separas can actually separate these structural maintenance of chromosome proteins and once these proteins are gone the chromosomes now can be separated properly and that really happens in during the anaphase State this is the normal scenario let's see if there is an unequal tension so this tension tension sensing is really important so this is the normal situation and let's say there is an unequal tension so there are bunch of tens tension sensors sitting near the region of the Kinto cor and that can trigger the activation of many molecules such as mad one mad 2 so these mad proteins are actually important sensors that can inhibit APC now if APC is inhibited that there is nobody to degrade securin now once securin is not degraded securin holds the separas complex and separas complex cannot separate it and thereby the chromosome separation doesn't happen at this point so again it waits till this tension normalize and then the segregation happens so this would ensure an equal segregation of chromosome now this concept that we discussed all the checkpoints are nicely described in the uh molecular biology of the cell by Harve Lish and all these concepts are taken from this book so you can quickly visit that chapter and take a quick revision so I hope this video was useful if you like this video give it a quick thumbs up you can get more notes and flash cards in our Facebook page or Instagram page you can support our Channel using super TRS you can pay via PTM PayPal or UPI see you in next video