Alberts Bray Hopkin Johnson Lewis Raff Roberts Walter
Essential Cell Biology FOURTH EDITION
Chapter 18 The Cell-Division Cycle
Copyright Garland Science 2014
CHAPTER CONTENTS OVERVIEW OF THE CELL CYCLE pp.604-607 THE CELL-CYCLE CONTROL SYSTEM pp.607-613 G1 PHASE pp.613-616 S PHASE pp.616-618 M PHASE pp.618-620 MITOSIS pp.621-629 CYTOKINESIS pp.630-633 CONTROL OF CELL NUMBERS AND CELL SIZE pp.633-641 OVERVIEW OF THE CELL CYCLE The Eukaryotic Cell Cycle Usually Includes Four Phases A Cell-Cycle Control System Triggers the Major Processes of the Cell Cycle Cell-Cycle Control is Similar in All Eukaryotes OVERVIEW OF THE CELL CYCLE The Eukaryotic Cell Cycle Usually Includes Four Phases A Cell-Cycle Control System Triggers the Major Processes of the Cell Cycle Cell-Cycle Control is Similar in All Eukaryotes OVERVIEW OF THE CELL CYCLE The Eukaryotic Cell Cycle Usually Includes Four Phases M phase Mitosis Prophase, metaphase, anaphase, telophase Cytokinesis Interphase G1 Gap 1 S phase DNA synthesis or replication G2 Gap 2 OVERVIEW OF THE CELL CYCLE The Eukaryotic Cell Cycle Usually Includes Four Phases A Cell-Cycle Control System Triggers the Major Processes of the Cell Cycle Cell-Cycle Control is Similar in All Eukaryotes OVERVIEW OF THE CELL CYCLE A Cell-Cycle Control System Triggers the Major Processes of the Cell Cycle Cell-Cycle timing and duration is controlled by a cell cycle control system Employs several checkpoints G1/S Restriction point (Start in yeast) confirms that the environment is favorable for proliferation before committing to DNA replication If inadequate> G0 G2/M confirms that the DNA is undamaged and fully replicated M phase checkpoint (boundary between Metaphase and Anaphase) ensures that the duplicated chromosomes are properly attached to the mitotic spindle OVERVIEW OF THE CELL CYCLE The Eukaryotic Cell Cycle Usually Includes Four Phases A Cell-Cycle Control System Triggers the Major Processes of the Cell Cycle Cell-Cycle Control is Similar in All Eukaryotes OVERVIEW OF THE CELL CYCLE Cell-Cycle Control is Similar in All Eukaryotes The time required to complete the cell cycle can vary greatly between organisms Also between cell types within the same organism Most of the machinery and mechanism to drive and regulate the cell cycle are homologous between organisms Much of our knowledge of cell cycle regulators in human cells comes from the study of other organisms Including yeast, amphibians, and even prokaryotes THE CELL-CYCLE CONTROL SYSTEM The Cell-Cycle Control System Depends on Cyclically Activated Protein Kinases called CDKs Different CyclinCDK Complexes Trigger Different Steps in the Cell Cycle Cyclin Concentrations are Regulated by Transcription and by Proteolysis The Activity of CyclinCDK Complexes Depends on Phosphorylation and Dephosphorylation CDK Activity Can be Blocked by CDK Inhibitor Proteins The Cell-Cycle Control System Can Pause the Cycle in Various Ways THE CELL-CYCLE CONTROL SYSTEM The Cell-Cycle Control System Depends on Cyclically Activated Protein Kinases called CDKs Protein kinases that regulate the cell cycle are present throughout the life cycle of a cell Their activity, however, is cyclical Activity is controlled, in part, by cyclin proteins Therefore these kinases are classified as cyclin-dependent kinases (CDKs) Cyclin proteins are produced (via transcription and translation) at appropriate times during the cell cycle SeeMovie18.1 THE CELL-CYCLE CONTROL SYSTEM The Cell-Cycle Control System Depends on Cyclically Activated Protein Kinases called CDKs Different CyclinCDK Complexes Trigger Different Steps in the Cell Cycle Cyclin Concentrations are Regulated by Transcription and by Proteolysis The Activity of CyclinCDK Complexes Depends on Phosphorylation and Dephosphorylation CDK Activity Can be Blocked by CDK Inhibitor Proteins The Cell-Cycle Control System Can Pause the Cycle in Various Ways THE CELL-CYCLE CONTROL SYSTEM Different CyclinCDK Complexes Trigger Different Steps in the Cell Cycle There are several types of cyclins as well as several types of CDKs in eukaryotic cells Different arrangements of cyclin-CDK partnerships regulate different stages of the cell cycle E.g., M cyclin along with its CDK makes M-CDK and controls entry into mitosis E.g., S cyclins + CDK form S-CDK for entry into S phase THE CELL-CYCLE CONTROL SYSTEM The Cell-Cycle Control System Depends on Cyclically Activated Protein Kinases called CDKs Different CyclinCDK Complexes Trigger Different Steps in the Cell Cycle Cyclin Concentrations are Regulated by Transcription and by Proteolysis The Activity of CyclinCDK Complexes Depends on Phosphorylation and Dephosphorylation CDK Activity Can be Blocked by CDK Inhibitor Proteins The Cell-Cycle Control System Can Pause the Cycle in Various Ways THE CELL-CYCLE CONTROL SYSTEM Cyclin Concentrations are Regulated by Transcription and by Proteolysis As with any protein, the concentration of a cyclin in a cell is determined by transcription and degradation Gradual increase due to transcription Sudden decline due to targeted proteolysis E.g., the abrupt degradation of M and S cyclins during M phase depends on the anaphase- promoting complex (APC). This complex tags these cyclins with a chain of ubiquitin. Directs cyclins to proteasomes where they are rapidly degraded Cdk becomes inactive THE CELL-CYCLE CONTROL SYSTEM The Cell-Cycle Control System Depends on Cyclically Activated Protein Kinases called CDKs Different CyclinCDK Complexes Trigger Different Steps in the Cell Cycle Cyclin Concentrations are Regulated by Transcription and by Proteolysis The Activity of CyclinCDK Complexes Depends on Phosphorylation and Dephosphorylation CDK Activity Can be Blocked by CDK Inhibitor Proteins The Cell-Cycle Control System Can Pause the Cycle in Various Ways THE CELL-CYCLE CONTROL SYSTEM The Activity of CyclinCDK Complexes Depends on Phosphorylation and Dephosphorylation It is not only the presence of cyclins that facilitates CDK activity Often, cyclin-CDK complexes contain inhibitory phosphates Removal of such phosphates by phosphatases activates the complex Thus, protein kinases and phosphatases regulate the activity of specific cyclinCdk complexes and help control progression through the cell cycle THE CELL-CYCLE CONTROL SYSTEM The Cell-Cycle Control System Depends on Cyclically Activated Protein Kinases called CDKs Different CyclinCDK Complexes Trigger Different Steps in the Cell Cycle Cyclin Concentrations are Regulated by Transcription and by Proteolysis The Activity of CyclinCDK Complexes Depends on Phosphorylation and Dephosphorylation CDK Activity Can be Blocked by CDK Inhibitor Proteins The Cell-Cycle Control System Can Pause the Cycle in Various Ways THE CELL-CYCLE CONTROL SYSTEM CDK Activity Can be Blocked by CDK Inhibitor Proteins CDK Inhibitor proteins (CDKIs) Block assembly of cyclin-CDK complexes Block activity of assembled cyclin-CDK complexes E.g., Some Cdk inhibitor proteins, help maintain Cdks in an inactive state during the G1 phase of the cycle Delay progression into S phase Pausing at this transition point in G1 gives the cell more time to grow, or allows it to wait until extracellular conditions are favorable for division. THE CELL-CYCLE CONTROL SYSTEM The Cell-Cycle Control System Depends on Cyclically Activated Protein Kinases called CDKs Different CyclinCDK Complexes Trigger Different Steps in the Cell Cycle Cyclin Concentrations are Regulated by Transcription and by Proteolysis The Activity of CyclinCDK Complexes Depends on Phosphorylation and Dephosphorylation CDK Activity Can be Blocked by CDK Inhibitor Proteins The Cell-Cycle Control System Can Pause the Cycle in Various Ways THE CELL-CYCLE CONTROL SYSTEM The Cell-Cycle Control System Can Pause the Cycle in Various Ways To ensure conditions are appropriate and the events occur in the correct order E.g., At the G1-to-S transition, it uses Cdk inhibitors to keep cells from entering S phase and replicating their DNA E.g., At the G2-to-M transition, it suppresses the activation of M-Cdk by inhibiting the phosphatase required to activate the Cdk E.g., It can delay the exit from mitosis by inhibiting the activation of APC, thus preventing the degradation of M cyclin G1 PHASE CDKs are Stably Inactivated in G1 Mitogens Promote the Production of the Cyclins that Stimulate Cell Division DNA Damage Can Temporarily Halt Progression Through G1 Cells Can Delay Division for Prolonged Periods by Entering Specialized Nondividing States G1 PHASE CDKs are Stably Inactivated in G1 Mitogens Promote the Production of the Cyclins that Stimulate Cell Division DNA Damage Can Temporarily Halt Progression Through G1 Cells Can Delay Division for Prolonged Periods by Entering Specialized Nondividing States G1 PHASE CDKs are Stably Inactivated in G1
All the active cyclin-CDK complexes from M
phase need to be inactivated If not, a new round of S-phase and M phase with begin with a brief G1 phase Requires elimination of cyclins Blocking the production of new cyclins Activity of CDKIs to inhibit remaining cyclin-CDK complexes G1 PHASE CDKs are Stably Inactivated in G1 Mitogens Promote the Production of the Cyclins that Stimulate Cell Division DNA Damage Can Temporarily Halt Progression Through G1 Cells Can Delay Division for Prolonged Periods by Entering Specialized Nondividing States G1 PHASE Mitogens Promote the Production of the Cyclins that Stimulate Cell Division Mammalian cells typically require mitogens to stimulate cell division Extracellular signal molecules Without which the cell will withdraw from the cell cycle For days, weeks, months or even permanently Mitogens activate signaling pathways that lead to synthesis of G1 cyclins, G1-S cyclins, and other proteins involved in DNA synthesis etc., The buildup of these cyclins triggers a wave of G1/S-Cdk activity, which ultimately relieves the negative controls that otherwise block progression from G1 to S phase G1 PHASE CDKs are Stably Inactivated in G1 Mitogens Promote the Production of the Cyclins that Stimulate Cell Division DNA Damage Can Temporarily Halt Progression Through G1 Cells Can Delay Division for Prolonged Periods by Entering Specialized Nondividing States G1 PHASE DNA Damage Can Temporarily Halt Progression Through G1 The DNA damage repair pathway in G1 is well understood DNA damage leads to increased transcription and activity of p53 A transcription regulator Up-regulates transcription of CDKI: p21 p21 binds G1/S-CDK and S-CDK to inhibit them G1 cell cycle arrest allows time for DNA repair If repair is not done, p53 up-regulates proteins involved in apoptosis p53 is mutated in almost 50% of cancers! SeeMovie18.3 G1 PHASE CDKs are Stably Inactivated in G1 Mitogens Promote the Production of the Cyclins that Stimulate Cell Division DNA Damage Can Temporarily Halt Progression Through G1 Cells Can Delay Division for Prolonged Periods by Entering Specialized Nondividing States G1 PHASE Cells Can Delay Division for Prolonged Periods by Entering Specialized Nondividing States 1.Permanent withdrawal is common in multicelllular organisms Terminal differentiation (e.g., nerve cells, muscle cells, etc.) the cell-cycle control system is dismantled completely and genes encoding the relevant cyclins and Cdks are irreversibly shut down. 2.Temporary withdrawal (in the absence of mitogens) G0 Still retain the ability to assemble the cell cycle control system S PHASE S-CDK Initiates DNA Replication and Blocks Re-Replication Incomplete Replication Can Arrest the Cell Cycle in G2 S PHASE S-CDK Initiates DNA Replication and Blocks Re-Replication
Preparation for S phase begins early in G1
Origins of replication serve as landing sites for replication protein machinery Origin Recognition Complex (ORC) is assembled throughout the cell cycle Cdc6 is recruited to the ORC as levels rise during G1 These proteins recruit DNA helicase Form the prereplicative complex The signal to start replication comes from S-Cdk late in G1 During S phase, S-CDK activates DNA helicase to recruit the rest of the replication fork machinery Phosphorylated Cdc6 is marked for degradation S PHASE S-CDK Initiates DNA Replication and Blocks Re-Replication Incomplete Replication Can Arrest the Cell Cycle in G2 S PHASE Incomplete Replication Can Arrest the Cell Cycle in G2 Earlier we saw the M-Cdk is inhibited by phosphorylation To initiate mitosis the phosphates must be removed Activating phosphatase Cdc25 When DNA damage occurs during S phase or DNA replication is stalled, Cdc25 is inhibited M-Cdk is inactive Cells remain in G2 M PHASE M-CDK Drives Entry Into M Phase and Mitosis Cohesins and Condensins Help Configure Duplicated Chromosomes for Separation Different Cytoskeletal Assemblies Carry Out Mitosis and Cytokinesis M Phase Occurs in Stages M PHASE M-CDK Drives Entry Into M Phase and Mitosis M-Cdk complexes accumulate throughout G2 Not active until the end of G2 Cdc25 must remove inhibitory phosphates M-Cdk activates more cdc25 resulting in increased amounts of M-Cdk activation Also, M-Cdk inhibites Wee1 (an inhibitory kinase) M-Cdk helps prepare the duplicated chromosomes for segregation M-Cdk induces the assembly of the mitotic spindle M PHASE M-CDK Drives Entry Into M Phase and Mitosis Cohesins and Condensins Help Configure Duplicated Chromosomes for Separation Different Cytoskeletal Assemblies Carry Out Mitosis and Cytokinesis M Phase Occurs in Stages M PHASE Cohesins and Condensins Help Configure Duplicated Chromosomes for Separation Visible condensation of chromosomes marks the beginning of mitosis Facilitated by condensin proteins Which are activated through phosphorylation by M-Cdk Cohesins are also critical for chromosome structure Hold sister chromatids together during S phase Remain intact into anaphase of mitosis M PHASE M-CDK Drives Entry Into M Phase and Mitosis Cohesins and Condensins Help Configure Duplicated Chromosomes for Separation Different Cytoskeletal Assemblies Carry Out Mitosis and Cytokinesis M Phase Occurs in Stages M PHASE Different Cytoskeletal Assemblies Carry Out Mitosis and Cytokinesis 1.Mitotic spindle Carries out nuclear division (mitosis) Microtubules and microtubule associated proteins E.g., motor proteins 2.Contractile ring Carries out cytoplasmic division (cytokinesis) Actin and myosin filaments Assembles just beneath the plasma membrane late in mitosis Both disassemble rapidly SeeMovie18.4and18.5 M PHASE M-CDK Drives Entry Into M Phase and Mitosis Cohesins and Condensins Help Configure Duplicated Chromosomes for Separation Different Cytoskeletal Assemblies Carry Out Mitosis and Cytokinesis M Phase Occurs in Stages M PHASE M Phase Occurs in Stages Mitosis Prophase Prometaphase Metaphase Anaphase Telophase Cytokinesis The final stage of M phase Begins before mitosis ends MITOSIS Centrosomes Duplicate To Help Form the Two Poles of the Mitotic Spindle The Mitotic Spindle Starts to Assemble in Prophase Chromosomes Attach to the Mitotic Spindle at Prometaphase Chromosomes Assist in the Assembly of the Mitotic Spindle Chromosomes Line Up at the Spindle Equator at Metaphase MITOSIS Proteolysis Triggers Sister-Chromatid Separation at Anaphase Chromosomes Segregate During Anaphase An Unattached Chromosome Will Prevent Sister-Chromatid Separation The Nuclear Envelope Re-forms at Telophase MITOSIS Centrosomes Duplicate To Help Form the Two Poles of the Mitotic Spindle The Mitotic Spindle Starts to Assemble in Prophase Chromosomes Attach to the Mitotic Spindle at Prometaphase Chromosomes Assist in the Assembly of the Mitotic Spindle Chromosomes Line Up at the Spindle Equator at Metaphase MITOSIS Centrosomes Duplicate To Help Form the Two Poles of the Mitotic Spindle The centrosome is the principal microtubule- organizing center in animal cells. It duplicates to form the two poles of the mitotic spindle Duplication begins as DNA replication begins Regulated by the same CDKs: G1/S-Cdk and S- Cdk Initially both copies remain together As mitosis begins they separate to opposite sides of the nucleus They nucleate a radial array of microtubules in the process Aster Centrosome cycle: the process of centrosome duplication and separation MITOSIS Centrosomes Duplicate To Help Form the Two Poles of the Mitotic Spindle The Mitotic Spindle Starts to Assemble in Prophase Chromosomes Attach to the Mitotic Spindle at Prometaphase Chromosomes Assist in the Assembly of the Mitotic Spindle Chromosomes Line Up at the Spindle Equator at Metaphase MITOSIS The Mitotic Spindle Starts to Assemble in Prophase Formation depends on dynamic instability of microtubules (MTs) At start of mitosis stability of MTs decreases In part because M-Cdk phosphorylates MAPs that influence the stability of MTs Some MTs growing from one centrosome interact with those from the other centrosome Stabilizes the MTs; prevents depolymerization Joins the two sets of MTs forming the basic framework of the mitotic spindle The two centrosomes are now called spindle poles The interacting MTs are called interpolar MTs Motor proteins help cross-link the 2 sets of MTs SeeMovie18.6 MITOSIS Centrosomes Duplicate To Help Form the Two Poles of the Mitotic Spindle The Mitotic Spindle Starts to Assemble in Prophase Chromosomes Attach to the Mitotic Spindle at Prometaphase Chromosomes Assist in the Assembly of the Mitotic Spindle Chromosomes Line Up at the Spindle Equator at Metaphase MITOSIS Chromosomes Attach to the Mitotic Spindle at Prometaphase Prometaphase starts abruptly with the disassembly of the nuclear envelope Triggered by phophorylation and disassembly of nuclear pore proteins and IF proteins of the nuclear lamina Spindle MTs access and bind to chromosomes At kinetochores Protein complexes at the centromere of each chromosome (assemble during late prophase) One per sister chromatid Bipolar attachment (i.e., bi-orientation) MITOSIS Centrosomes Duplicate To Help Form the Two Poles of the Mitotic Spindle The Mitotic Spindle Starts to Assemble in Prophase Chromosomes Attach to the Mitotic Spindle at Prometaphase Chromosomes Assist in the Assembly of the Mitotic Spindle Chromosomes Line Up at the Spindle Equator at Metaphase MITOSIS Chromosomes Assist in the Assembly of the Mitotic Spindle Chromosomes are not passive in the process of spindle assembly Help stabilize and organize MTs into functional mitotic spindles In cells without centrosomes (e.g., plant cells) the chromosomes nucleate MTs and motor proteins move and arrange the MTs and chromosomes into bipolar spindle MITOSIS Centrosomes Duplicate To Help Form the Two Poles of the Mitotic Spindle The Mitotic Spindle Starts to Assemble in Prophase Chromosomes Attach to the Mitotic Spindle at Prometaphase Chromosomes Assist in the Assembly of the Mitotic Spindle Chromosomes Line Up at the Spindle Equator at Metaphase MITOSIS Chromosomes Line Up at the Spindle Equator at Metaphase Alignment of chromosomes at equator of the cells forms the metaphase plate Defines the beginning of metaphase Involves dynamic instability of MTs as well as motor protein function The chromosomes are held there under tension SeeMovie18.7 MITOSIS Proteolysis Triggers Sister-Chromatid Separation at Anaphase Chromosomes Segregate During Anaphase An Unattached Chromosome Will Prevent Sister-Chromatid Separation The Nuclear Envelope Re-forms at Telophase MITOSIS Proteolysis Triggers Sister-Chromatid Separation at Anaphase Anaphase begins with the breakage of the cohesin between sister chromatids Results in segregation of identical sets of chromosomes to opposite poles Cohesin is destroyed by the protease separase Separase is normally held in an inactive state by securin Securin is targeted for destruction by APC freeing separase to breakdown cohesin MITOSIS Proteolysis Triggers Sister-Chromatid Separation at Anaphase Chromosomes Segregate During Anaphase An Unattached Chromosome Will Prevent Sister-Chromatid Separation The Nuclear Envelope Re-forms at Telophase MITOSIS Chromosomes Segregate During Anaphase Chromosomes separate at a rate of 1 m/minute Movement is due to 2 independent processes by different parts of the mitotic spindle Anaphase A The kinetochore MTs shorten with the chromosomes attached Driven by MT depolymerization Anaphase B The spindle poles move apart Kinesins act on the long, overlapping interpolar MTs sliding the MTs from opposite poles past one another at the equator, pushing the spindle poles apart Dynein proteins, anchored to the cell cortex, pull the poles apart MITOSIS Proteolysis Triggers Sister-Chromatid Separation at Anaphase Chromosomes Segregate During Anaphase An Unattached Chromosome Will Prevent Sister-Chromatid Separation The Nuclear Envelope Re-forms at Telophase MITOSIS An Unattached Chromosome Will Prevent Sister- Chromatid Separation The M phase checkpoint is more appropriately called the spindle assembly checkpoint Inhibits activation of APC until bi-polar attachment of MTs to kinetochores Prevents non-disjunction MITOSIS Proteolysis Triggers Sister-Chromatid Separation at Anaphase Chromosomes Segregate During Anaphase An Unattached Chromosome Will Prevent Sister-Chromatid Separation The Nuclear Envelope Re-forms at Telophase MITOSIS The Nuclear Envelope Re-forms at Telophase Telophase Nuclear pore proteins and nuclear lamins are dephosphorylated Vesicles of nuclear membrane first cluster around individual chromosomes Fuse to re-form the nuclear envelope Nuclear envelope reassembles around each group of chromosomes Forms two daughter nuclei Nuclear pores pump in nuclear proteins Nucleus expands Condensed chromosomes decondense gene transcription resumes Mitotic spindle disassembles SeeMovie18.8 CYTOKINESIS The Mitotic Spindle Determines the Plane of Cytoplasmic Cleavage The Contractile Ring of Animal Cells Is Made of Actin and Myosin Filaments Cytokinesis in Plant Cells Involves the Formation of a New Cell Wall Membrane-Enclosed Organelles Must Be Distributed to Daughter Cells When a Cell Divides CYTOKINESIS The Mitotic Spindle Determines the Plane of Cytoplasmic Cleavage Cytokinesis is initiated during anaphase Furrowing occurs in plane perpendicular to the long axis of the mitotic spindle Cleavage furrow cuts between the two groups of chromosomes Overlapping interpolar MTs that form the central spindle recruit and activate proteins which signal to the cell cortex to initiate the assembly of the contractile ring midway between the spindle poles CYTOKINESIS The Mitotic Spindle Determines the Plane of Cytoplasmic Cleavage The Contractile Ring of Animal Cells Is Made of Actin and Myosin Filaments Cytokinesis in Plant Cells Involves the Formation of a New Cell Wall Membrane-Enclosed Organelles Must Be Distributed to Daughter Cells When a Cell Divides CYTOKINESIS The Contractile Ring of Animal Cells Is Made of Actin and Myosin Filaments Contractile ring is made of an overlapping array of actin and myosin filaments Assembles at anaphase Attached to membrane-associated proteins (MAPS) on cytosolic face of the plasma membrane Contractile ring is a transient structure Disassembles following cytokinesis Cells tend to round up in shape Due to phosphorylation of integrins which weakens their grip on substratum CYTOKINESIS The Mitotic Spindle Determines the Plane of Cytoplasmic Cleavage The Contractile Ring of Animal Cells Is Made of Actin and Myosin Filaments Cytokinesis in Plant Cells Involves the Formation of a New Cell Wall Membrane-Enclosed Organelles Must Be Distributed to Daughter Cells When a Cell Divides CYTOKINESIS Cytokinesis in Plant Cells Involves the Formation of a New Cell Wall The final form of the new plant cells is determined by the plane of cell division along with cell enlargement The new cell wall starts to form at the beginning of telophase Guided by a structure called the phragmoplast Formed by the remains of the interpolar MTs at the equator of the old mitotic spindle Small membrane-bound vesicles from the Golgi carry polysaccharides and glycoprotein for cell-wall matrix Carried on MTs Build from center of cell out toward periphery Eventually cellulose microfibrils are laid down within the matrix to complete the cell wall CYTOKINESIS The Mitotic Spindle Determines the Plane of Cytoplasmic Cleavage The Contractile Ring of Animal Cells Is Made of Actin and Myosin Filaments Cytokinesis in Plant Cells Involves the Formation of a New Cell Wall Membrane-Enclosed Organelles Must Be Distributed to Daughter Cells When a Cell Divides CYTOKINESIS Membrane-Enclosed Organelles Must Be Distributed to Daughter Cells When a Cell Divides Self explanatory (lol)
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