Transcript Chapter 11
Chapter 11 Cell Cycle Regulation By Srinivas Venkatram, Kathleen L. Gould, & Susan L. Forsburg 11.1 Introduction • A cell contains all the information necessary for making a copy of itself during a cell division cycle. • The eukaryotic cell division cycle (cell cycle) is composed of an ordered set of events. – It results in the generation of two copies of a preexisting cell. 11.1 Introduction • The cell cycle is partitioned into distinct phases during which different events take place. • Two important phases of the cell cycle are: – Replication of a cell’s chromosomes – Chromosome segregation 11.2 There are several experimental systems used in cell cycle analyses • Studies in a wide variety of organisms have contributed to our knowledge of cell cycle regulation. – Each has advantages and disadvantages. • Genetic analyses of the cell cycle in yeasts identified conserved cell cycle regulators. 11.2 There are several experimental systems used in cell cycle analyses • Biochemical analyses of protein complexes from multicellular organisms complemented the genetic studies of single-celled organisms. • Synchronized populations of cells are important for analyzing cell cycle events. 11.3 The cell cycle requires coordination between events • Checkpoints act to: – ensure error-free completion of DNA replication before entry into mitosis – maintain the temporal coordination of S and M phases 11.4 The cell cycle as a cycle of CDK activities • CDKs: – are the master regulators of the cell cycle – are active only when complexed with cyclin proteins 11.4 The cell cycle as a cycle of CDK activities • Cyclins derive their name from the periodic oscillation of their protein levels during the cell cycle. • A CDK can be partnered with different cyclins during different phases of the cell cycle. 11.5 CDK-cyclin complexes are regulated in several ways • CDK-cyclin complexes are regulated by: – phosphorylation – inhibitory proteins – proteolysis – subcellular localization 11.6 Cells may exit from and reenter the cell cycle • Cells may be maintained in a nondividing state called quiescence, or G0. • Quiescent cells may be stimulated to return to the cell cycle by environmental cues. 11.6 Cells may exit from and reenter the cell cycle • Cells reenter the cell cycle primarily at G1. • Cells may also permanently leave the cell cycle by differentiating into a specialized cell type. • Some cells are programmed to selfdestruct by apoptosis. 11.7 Entry into cell cycle is tightly regulated • Cell divisions are not continuous. – They are controlled by: • external stimuli • nutrient availability • Cells detect the presence of chemical signals in their environment. 11.7 Entry into cell cycle is tightly regulated • Extracellular signals can elicit an intracellular biochemical response that results in either: – entry into the cell cycle or – cell cycle arrest in a G1/G0 phase 11.8 DNA replication requires the ordered assembly of protein complexes • Replication occurs after cells progress through the restriction point or START. • Replication: – is regulated in a stepwise fashion – is coordinated with the completion of mitosis 11.8 DNA replication requires the ordered assembly of protein complexes • Replication occurs at origins that may be defined by: – Sequence or – Position or – Spacing mechanisms • Initiation occurs only at origins that are licensed to replicate. • Once fired, origins cannot be reused until the next cell cycle. 11.9 Mitosis is orchestrated by several protein kinases • The transition from G2 to M is a major control point in many eukaryotic cells. • Activation of several protein kinases is associated with the G2-M transition. 11.10 Many morphological changes occur during mitosis • The nuclear and cytoskeletal architectures change dramatically for mitosis. • Mitotic kinases are required for the proper execution of mitotic events such as: – – – – nuclear envelope breakdown chromosome condensation and segregation spindle assembly cytokinesis 11.11 Mitotic chromosome condensation and segregation depend on condensin and cohesin • In preparation for separation, chromosomes: – condense – move to the center of the mitotic spindle • Chromosomes become attached to microtubules emanating from opposite poles of the spindle through specialized regions called kinetochores. 11.11 Mitotic chromosome condensation and segregation depend on condensin and cohesin • Cohesion that binds sister chromatids together is released. – This enables their separation. • Independent sister chromatids are further separated in space before cytokinesis. 11.12 Exit from mitosis requires more than cyclin proteolysis • Exit from mitosis requires inactivation of Cdk1. • Mitotic exit also involves the reversal of Cdk1 phosphorylation. 11.12 Exit from mitosis requires more than cyclin proteolysis • Inactivation of Cdk1 and reversal of Cdk1 phosphorylation are coordinated with: – disassembly of the mitotic spindle – cytokinesis 11.13 Checkpoint controls coordinate different cell cycle events • Cell cycle events are coordinated with one another. • The coordination of cell cycle events is achieved by the action of specific biochemical pathways called checkpoints. – Checkpoints delay cell cycle progression if a previous cell cycle event has not been completed. 11.13 Checkpoint controls coordinate different cell cycle events • Checkpoints may be essential only when cells are stressed or damaged. – They may also act during a normal cell cycle to ensure proper coordination of events. 11.14 DNA replication and DNA damage checkpoints monitor defects in DNA metabolism • Incomplete and/or defective DNA replication activates a cell cycle checkpoint. 11.14 DNA replication and DNA damage checkpoints monitor defects in DNA metabolism • Damaged DNA activates a different checkpoint that shares some components with the replication checkpoint. • The DNA damage checkpoint halts the cell cycle at different stages depending on the stage during which the damage occurred. 11.15 The spindle assembly checkpoint monitors defects in chromosomemicrotubule attachment • The mitotic spindle attaches to individual kinetochores of chromosomes during mitosis. • Proper attachment of microtubules to kinetochores is a prerequisite for chromosome segregation. 11.15 The spindle assembly checkpoint monitors defects in chromosome-microtubule attachment • Defects in spindle-MT attachment are sensed by the “spindle assembly checkpoint.” • This checkpoint subsequently halts the metaphase-anaphase transition to prevent errors in sister chromatid separation. 11.16 Cell cycle deregulation can lead to cancer • Proto-oncogenes encode proteins that drive cells into the cell cycle. • Tumor suppressor genes encode proteins that restrain cell cycle events. • Mutations in proto-oncogenes, tumor suppressor genes, or checkpoint genes may lead to cancer.