229.Cellcycley110216 - DNA Replica,on Cell cycle and...

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Unformatted text preview: DNA Replica,on, Cell cycle, and Mitosis. 19 11/2/16 DNA replica,on and the cell cycle. The Eukaryo,c cell cycle. • Cell growth and division proceeds in an ordered and cyclical manner – cell cycle. • Protein and other bio-­‐[email protected] processes leading to cellular and organellar growth occur in the G (gap) phases . • DNA synthesis occurs in the S phase. • Cell division and mitosis occur in the M phase. DNA synthesis is semi-­‐ conserva,ve. • During [email protected] the DNA strands unwind and each serves as a template for the synthesis of a new strand. • When the helix is duplicated it is composed of one old and one new strand. Replica,on of circular DNA. • DNA [email protected] commences at a defined region called the origin of replica,on. • It proceeds bi-­‐direc,onally to produce 2 copies of the circular DNA ( theta [email protected]) . • The 2 circular copies are separated by a topoisomerase. Binary fission: Cell division in prokaryotes. • The 2 copies of the genome move towards opposite ends of the cell. • A cell membrane then divides the 2 daughter cells from each other. The double helix-­‐ contd . • [email protected] [email protected] [email protected] from [email protected] [email protected] origins-­‐why? • Origins exhibit ,ssue and temporal specificity. [email protected] [email protected] regions are replicated earlier in S phase. • [email protected] forks also move [email protected] and fuse when they meet each other. Licensing proteins ensure proper replica,on. • [email protected] sets of proteins bind [email protected] to origins in order to [email protected] it. • They are also regulated at the protein level to prevent origins from firing more than once during the cell cycle. DNA replica,on occurs in a 5’ to 3’ direc,on. • [email protected] are added in a 5’ to 3’ [email protected] to a growing chain. • The energy from breaking P-­‐P bond is used for the synthesis of the phosphodiester bond. • So what happens to the other strand ? DNA synthesis occurs con,nuously and discon,nuously. • Pulse labeling of the new strands shows that some of it is composed of short strands. • The short strands accumulate in the absence of DNA ligase. Leading and lagging strands of DNA synthesis. • DNA synthesis can only occur in a 3’ to 5’ [email protected] One (leading) strand is synthesized con,nuously as the [email protected] fork moves along the DNA. • The other strand is synthesized discon,nuously as short Okazaki fragments (1-­‐2 kb long) that make up the lagging strand. Looping of the lagging strand template allows the 2 strands to be in register. • Looping of the lagging strand allows both strands to be replicated in the same [email protected] by the same replisome. DNA synthesis occurs from RNA primers. •  DNA polymerases can only extend an [email protected] strand. • Synthesis of short complementary RNA molecules [email protected] each DNA strand synthesis. •  The RNA primers are degraded and replaced by DNA sequences when when one preceding strand reaches the next one. Proof reading func,on of DNA polymerases.. •  DNA polymerases also possess a 3’ to 5’ exonuclease ac?vity which allows them to chew back and remove mis-­‐incorporated bases. •  What is the benefit of this [email protected] ? The end replica,on problem. •  The removal of RNA primers shortens the lagging strand at each end of the chromosome. Effect on chromosome [email protected]? •  Extensive shortening of chromosomes leads cell senescence and death. Why ? Telomerase and solu,on to the end replica,on problem. •  Some cells can elongate shortened chromosomes by [email protected]@ng telomerase. •  What is the consequence of telomere [email protected] and why? Mitosis. Mitosis-­‐contd. Nuclear compartmentaliza,on of the genome. •  Cell division is usually coordinated with mitosis. •  A cleavage furrow forms (late anaphase) along the spindle mid zone. •  It consists of a contrac,le ring composed of ac,n filaments. •  [email protected] [email protected] and ring @ghtening are driven by GTP binding rho proteins and myosin motors. •  The ring finally separates the two daughter cells. Cell fusion experiments demonstrate mechanisms driving the cell cycle. Factors controlling the cell cycle. •  Cytoplasmic injecton experiments further showed that [email protected] cell extracts can induce interphase or immature cells to ectopically [email protected] mitosis. Oscilla,ng ac,vity of matura,on promo,ng factor. Cyclin-­‐cdk complexes control cell cycle progression. •  Different stages of cell cycle are driven by cyclin dependent kinases (cdks) and their regulatory cyclin subunits . •  Cdk levels remain steady but their ac,vity fluctuates with the level of the cognate cyclin. •  Levels of cyclin proteins are @ghtly regulated during the cell cycle. They are rapidly degraded once their task is done. Regula,on of the cell cycle by checkpoints. •  Cell cycle is irreversible. [email protected] regulated by checkpoints. •  Check points ensure that steps have been properly executed and cell is ready to progress. •  The checkpoints either allow the cycle to proceed or stall @ll problem is resolved. Major cell cycle checkpoints. •  Restric,on point controls entry into the cell cycle i.e. G1/S transi,on. It is controlled by the Rb protein and regulated by growth factors. •  DNA damage checkpoint controls passage through the S phase into G2. It is controlled by p53 which acts as a damage sensor and [email protected] repair mechanisms. •  Mito,c spindle checkpoint determines [email protected] from metaphase to anaphase. It is controlled by the anaphase promo,ng complex which monitors correct alignment of chromosomes at the metaphase plate and tension in kinetochore fibers. Determines [email protected] of chromosomes....
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