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Home , Cdc6, Cell cycle checkpoint, Cyclin B, DBF4, Metaphase, Prophase

RnDSy-lu-2945 Regulation of the Cycle and DNA Damage-Induced Checkpoint Activation

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Regulators of Progression CellSensors Cycle Checkpoint P Activating P Inactivating Phosphorylation

G2 - Second Gap Phase Sensors Mammalian (s) Complete Name Basic Checkpoint Function G1 - First Gap Phase Mammalian Protein(s) Complete Name Basic Cell Cycle Function Sensors: Proteins that recognize and bind to damaged DNA to initiate signal transduction pathways that inhibit cell cycle progression and promote DNA repair or . 14th DEAE elution fraction Mammalian Protein(s) Complete Name Basic Cell Cycle Function 14-3-3 Sequesters CDC25s or CDK1- B in the cytoplasm to inhibit the G2/M transition Sensors CAK CDK-Activating Involved in CDK-Cyclin activation; Phosphorylates T160/161 of CDKs and 3.3 migration pattern Rad9-Rad1-Hus1 (9-1-1 Complex) Radiation Sensitive 9-Radiation Sensitive 1-Hydroxyurea Sensitive 1 Heterotrimeric DNA-binding complex that coordinates checkpoint signaling and DNA repair CAK CDK-Activating Kinase Involved in CDK-Cyclin activation; Phosphorylates T160/161 of CDKs Sensors CDC25A Cycle 25A Dual-specificity that removes inhibitory phosphates at T14 and Y15 of CDKs g-H2AX H2A variant X Recognizes and binds to DNA double-strand breaks (DSBs) CDK-Cyclin complex activated at the G1/S transition; Phosphorylates Rb and other substrates Three different dual-specificity that promote the G2/M transition by removing inhibitory CDK2- Cyclin-Dependent Kinase 2-Cyclin E CDC25A,B,C Cell Division Cycle 25A, B, C to promote S phase phosphates from CDK1 at T14 and Y15 Mre11-Rad50-Nbs1 (M/R/N Complex) Meiotic Recombination 11-Radiation Sensitive 50-Nijmegen Breakage Syndrome 1 Recruits and activates ATM at DNA DSBs CDK1 - (CDC2) Cyclin-Dependent Kinase 1-Cyclin B CDK-Cyclin complex required for the G2/M transition; Phosphorylates multiple substrates to promote CDK4/6- Cyclin-Dependent Kinase 4/6-Cyclin D CDK-Cyclin complexes activated in G1 to promote cell cycle progression; Phosphorylate Rb and other substrates Rad17 Radiation Sensitive 17 Loads the 9-1-1 complex onto damaged DNA along with RFC2-5 CDK-Interacting Protein 1/ Family of proteins that includes , p27, and p57 which bind CDK/Cyclin complexes in the nucleus C-TAK1 CDC25C-Associated Kinase 1 that negatively regulates CDC25C to inhibit the G2/M transition CIP/KIP Membrane-Associated Tyrosine- Protein kinase that negatively regulates cytoplasmic CDK1-Cyclin B by inhibitory phosphorylation of CDK1 RFC2-5 2-5 Loads the 9-1-1 complex onto damaged DNA along with Rad17 CDK Inhibitory Protein 1 to inhibit CDK activity Myt1 and Threonine-specific CDC2 Inhibitory Kinase at T14 and Y15 E2 Promoter Binding Factor/ Protein complex that activates the transcription of whose products are important for promoting Mediators: Scaffolding proteins that form multiprotein complexes at sites of DNA damage to recruit transducers and maintain checkpoint activation. /DP Dimerization Partner DNA replication Protein kinase that phosphorylates and Cyclin B to promote their nuclear translocation at the mitotic Polo-like Kinase 1 53BP1 Binding Protein 1 Scaffolding protein at DNA DSBs; Recruits other checkpoint/repair proteins Hypophosphorylated form recruits histone deacetylase to the promoters of E2F-regulated genes to inhibit transition; Negatively regulates the Myt1 and Rb Protein kinase that negatively regulates CDK-Cyclin complexes in the nucleus by inhibitory phosphorylation their expression; Rb phosphorylation allows E2F-DP activity Wee1 Wee1 BRCA1 Breast 1 Scaffolding protein at DNA DSBs; DNA repair and recombination Wee1 Wee1 Protein kinase that negatively regulates CDK-Cyclin complexes by inhibitory phosphorylation of CDKs at Y15 of CDKs at Y15 Mediators Claspin Claspin Bridges ATR and Chk1 to facilitate Chk1 activation M phase - Mitosis Mediators S phase - DNA Replication Mammalian Protein(s) Complete Name Basic Cell Cycle Function MDC1 Mediator of DNA Damage Checkpoint 1 Scaffolding protein at DNA DSB sites; Recruits other checkpoint/repair proteins Mammalian Protein(s) Complete Name Basic Cell Cycle Function Chromosomal Passenger Complex (CPC) Mediators TopBP1 Binding Protein 1 Implicated in ATR activation; Binds to Rad9 in the 9-1-1 complex to promote ATR-mediated Chk1 phosphorylation Pre-Replication Complex (Pre-RC) Enzymatic core of the CPC; Mitotic kinase that ensures proper alignment; Replication involved in loading the MCM2-7 complex onto origins (ORI); Transducers:Mediators Kinases that are activated to transmit damage signals to effector molecules in the cell. Cell Division Cycle 6 Aurora B Aurora B Stabilizes - attachments; Required for lack of tension checkpoint response; Inhibits re-replication Regulates cytokinesis ATM Ataxia Telangiectasia-Mutated Phosphorylates multiple substrates in response to DNA DSBs Replication licensing factor involved in loading the MCM2-7 helicase complex onto origins; CDT1 CDC10-Dependent Transcript 1 Borealin Borealin Promotes binding of and INCENP in the CPC ATR: Phosphorylates multiple substrates in response to DNA damage that induces long stretches of RPA-coated ss-DNA such as stalled Inhibits re-replication ATR-ATRIP ATR: ATM and Rad3-related; ATRIP: ATR-Interacting Protein replication forks, or UV-induced DNA damage; ATRIP: Interacts with RPA and regulates the recruitment of ATR to sites of DNA damage Inhibitor of CDT1; Prevents origin licensing from S phase to metaphase by blocking the loading of the INCENP Inner Centromere Protein Stabilizes the CPC; Regulates Aurora B activation Geminin MCM2-7 helicase complex Chk1 Checkpoint Kinase 1 Kinase activated by ATR via phosphorylation; Phosphorylates and inactivates CDC25s Localizes the CPC to or the ; Involved in spindle assembly checkpoint activation; Transducers MCM2-7 Minichromosome Maintenance 2-7 Hexameric protein complex that acts as a helicase to unwind DNA at origins of replication Survivin Survivin Required for the progression of cytokinesis Chk2 Checkpoint Kinase 2 Kinase activated by ATM via phosphorylation; Phosphorylates and inactivates CDC25s Regulates replication initiation and elongation by recruiting CDC45 and DNA pol a/ to origins; Transducers MCM10 Minichromosome Maintenance 10 Mitotic Checkpoint Complex (MCC) Stabilizes DNA pol a/Primase p38 MAPK p38 -Activated Protein Kinase Activated by different types of DNA damage; Implicated in the G2/M checkpoint E3 (Ub) that targets Cyclin B and for degradation leading to sister Transducers Hexameric protein complex that acts as a scaffold for the assembly of multiprotein pre-RCs APC/C Anaphase Promoting Complex/Cyclosome MAPKAPK-2 Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 Activated by p38 MAPK; Implicated in the G2/M checkpoint ORC Origin Recognition Complex separation in anaphase and mitotic exit at origins of replication Transducers Associates with unattached or kinetochores lacking tension; Recruits Bub-3 and BubR1 Effectors: Proteins that can directly prevent cell cycle progression when activated or inhibited by transducers. Origin Activation Bub-1 Budding Uninhibited by Benzimidazoles 1 CAK CDK-Activating Kinase Involved in CDK-Cyclin activation; Phosphorylates T160/161 of CDKs to inhibit CDC20 and APC/C activity p53 p53 Transcription factor; Primary regulator of cell cycle arrest and DNA repair, or initiation of apoptosis CDC7/DBF4 Cell Division Cycle 7/Dumbell Former 4 CDC7: Protein kinase required for the initiation of DNA replication; DBF4: Regulates CDC7 activity Bub-3 Budding Uninhibited by Benzimidazoles 3 Localizes Bub-1 and BubR1 to kinetochores Implicated in the Intra-S-phase checkpoint; Interacts with FANCD2 to mediate recombinational repair of DNA damage generated by IR, CDC25A Cell Division Cycle 25A Dual-specificity phosphatase that removes inhibitory phosphates at T14 and Y15 of CDKs BRCA1 Breast Cancer 1 Budding Uninhibited by Associates with unattached kinetochores or kinetochores lacking tension; Binds CDC20 to inhibit the Ub ligase crosslinking, or stalled replication forks Helicase co-factor essential for replication initiation and elongation; Loading at origins is required BubR1 CDC45 Cell Division Cycle 45 Benzimidazoles R1 activity of the APC/C for the association of DNA a/Primase CDC7/DBF4 Cell Division Cycle 7/Dumbell Former 4 CDC7: Protein kinase required for origin activation; DBF4: Regulates CDC7 activity CDK2-Cyclin E/A Cyclin-Dependent Kinase 2-Cyclin E/A CDK-Cyclin complexes required for origin activation in S phase CDC20 Cell Division Cycle 20 Activator and substrate adaptor of the APC/C CDC25A Cell Division Cycle 25A Protein phosphatase required for CDK dephosphorylation and activation; Implicated in the G1/S, Intra-S-phase, and G2/M checkpoints Origin Unwinding CENP-E Centromere Protein E Involved in the capture and stabilization of spindle by kinetochores CDC25B Cell Division Cycle 25B Protein phosphatase required for CDK dephosphorylation and activation; Implicated in the G2/M checkpoint DNA Pol a/Primase DNA Polymerase a/Primase Synthesizes primers de novo to initiate DNA replication Mitotic Arrest Deficient 1 Associates with unattached kinetochores; Recruits to inhibit CDC20 and APC/C Ub ligase activity CDC25C Cell Division Cycle 25C Protein phosphatase required for CDK dephosphorylation and activation; Implicated in the G2/M checkpoint Heterotrimeric protein complex that binds and stabilizes single-stranded DNA (ss-DNA) generated during RPA replication or as a result of DNA damage MAD2 Mitotic Arrest Deficient 2 Associates with unattached kinetochores; Binds to CDC20 to inhibit the Ub ligase activity of the APC/C CDKs Cyclin-Dependent Kinases Protein kinases required for progression through each stage of the cell cycle Elongation Sister Chromatid Separation FANCD2 Complementation Group D2 Implicated in the Intra-S-phase checkpoint; Interacts with BRCA1 to mediate the resolution of DNA crosslinks and stalled replication forks DNA Ligase DNA Ligase Ligates together during lagging strand replication CENP-A Centromere Protein A Histone H3 variant involved in centromere-kinetochore formation d e d e Implicated in the Intra-S-phase checkpoint as both an activator of ATM and an effector; Inhibits origin firing after specific types of DNA DNA Pol / DNA and DNA polymerases involved in elongation of a primed strand during leading and lagging strand replication Mre11-Rad50-Nbs1 (M/R/N Complex) Meiotic Recombination 11-Radiation Sensitive 50-Nijmegen Breakage Syndrome 1 FEN-1 -1 Removes the 5’ single-stranded flap formed by primer displacement during lagging strand replication Complex Cohesin Complex Protein complex that holds sister together damage by an unknown mechanism; DNA end- processing to facilitate DNA repair or recombination PCNA Proliferating Cell Nuclear Antigen factor for DNA polymerase d; Loaded onto DNA by RFC MCAK Mitotic Centromere-Associated Kinesin Microtubule depolymerizing activity; Contributes to the correction of defective kinetochore attachments Implicated in the Intra-S-phase checkpoint as part of the ATM-Nbs1-SMC1 branch; Unknown mechanism to inhibit origin firing SMC1 Structural Maintenance of 1 RFC Replication Factor C Clamp loading complex; Loads PCNA onto DNA Effectors after specific types of DNA damage; Sister-chromatid cohesion and recombination Securin Securin Inhibits to prevent the of Cohesin and sister chromatid separation Effectors Separase Separase Protease that cleaves Cohesin allowing to be pulled to opposite poles in anaphase NOTE: This poster conveys a general overview and should be considered neither comprehensive nor definitive. The details of this information are understood to be subject to interpretation. © R&D Systems 2009, 2015 Effectors Effectors

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