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5 public questions tagged with this topic.

Cell Cycle Regulation

Which of the following prevents mitotic exit if chromosomes are not properly aligned?

Accurate mitosis demands anaphase initiation strictly after all chromosomes achieve stable amphitelic attachment generating tension. The spindle assembly checkpoint monitors this criterion. Unattached kinetochores catalyze assembly of Mitotic Checkpoint Complex composed of Mad2 locked as C-Mad2, BubR1 ortholog of yeast Mad3, Bub3 and Cdc20 coactivator of APC/C. Within MCC, BubR1 provides pseudosubstrate motif inserting KEN boxes into Cdc20 binding pockets plus direct inhibition of APC/C central cavity, thereby preventing ubiquitination of securin and cyclin B. BubR1 also functions as protein kinase and scaffold recruiting PP2A-B56 phosphatase counteracting Aurora B at tensionless attachments and promoting establishment of correct bioriented connections. As long as even one kinetochore remains unattached, MCC production continues, suppressing mitotic exit and cytokinesis. Upon microtubule capture, dynein-mediated stripping of Mad1-Mad2 and p31comet-TRIP13 driven MCC disassembly terminates signal, permitting APC/C activation. Persistence of BubR1 mediated inhibition therefore prevents premature exit, safeguarding against aneuploidy, chromosome missegregation and cancer progression. This regulatory circuit illustrates integration of checkpoint kinases, ubiquitin ligases, phosphatases and structural proteins coordinating accurate cell division and preventing aneuploidy associated with tumorigenesis.

Ref: Musacchio, Spindle Assembly Checkpoint Structure of BubR1-MCC, Curr Biol 2015; NCBI Bookshelf, SAC component BubR1.

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Cell Cycle Regulation

Which of the following is NOT a function of CDK1-Cyclin B?

CDK1-Cyclin B, historically termed Maturation Promoting Factor, orchestrates early mitotic transformations upon nuclear translocation. Its catalytic subunit CDK1 becomes competent after binding Cyclin B, phosphorylation at Thr161 by CAK and dephosphorylation of inhibitory Thr14/Tyr15 by Cdc25C. Once active, it phosphorylates serine-threonine-proline motifs on diverse substrates: lamins A-C at Ser22, Ser392 causing depolymerization of intermediate filament network and nuclear envelope breakdown, condensin subunits Cap-D2, Cap-H2 stimulating chromosome condensation, Golgi matrix proteins GRASP65, GM130 leading to fragmentation, nucleolar proteins B23 and fibrillarin releasing ribosome biogenesis components, and microtubule regulators Eg5 kinesin, TPX2, NuMA driving bipolar spindle assembly and centrosome separation. Global transcription inhibition and cap-dependent translation downregulation also result from phosphorylation of TFDII and 4E-BP1 relatives. DNA replication initiation, however, depends on distinct S-phase kinases CDK2-Cyclin E, Cyclin A plus DDK Cdc7-Dbf4 phosphorylating MCM2-7 and Cdc45 loader, a process actively suppressed during mitosis when CDK1-Cyclin B is high and replication licensing factors degraded, explaining why replication cannot be assigned to mitotic complex. Additional feedback loops involving polo-like kinases, phosphatases and SCF-mediated degradation reinforce irreversibility and protect against premature progression that would compromise genome integrity and viability.

Ref: Morgan, The Cell Cycle: Principles of Control, Chapter 3, Mitotic CDK Functions; Nature Reviews, Mitotic Entry and Mitosis.

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Cell Cycle Regulation

The G1/S transition is tightly regulated by:

Commitment to S phase involves transcriptional and posttranslational steps driven by Cyclin E-CDK2 activity pulse. During early G1, Cyclin D-CDK4/6 initiates partial Rb phosphorylation after mitogen induction, allowing modest E2F-dependent synthesis of Cyclin E. Rising Cyclin E binds CDK2, fully activating kinase normally restrained by inhibitors p21 and p27. Cyclin E-CDK2 hyperphosphorylates Rb at additional sites, liberating large pool of E2F1-3 which amplify expression of Cyclin A, Cdc6, MCM helicase components, dihydrofolate reductase and Pol alpha. Concurrently Cyclin E-CDK2 phosphorylates p27 at Thr187 creating phosphodegron recognized by SCF-Skp2-Cks1, leading to degradation and reinforcement of CDK2 activity. It also phosphorylates NPAT regulator of histone genes, Cdc45 recruitment factors Treslin and RecQL4, directly promoting origin firing and replication complex assembly. Cyclin E levels then fall through autophosphorylation induced recognition by SCF-Fbw7 ligase, producing transient spike. Amplification of Cyclin E in cancers causes premature S entry, centrosome overduplication, replication stress and chromosome instability. Additional feedback loops involving polo-like kinases, phosphatases and SCF-mediated degradation reinforce irreversibility and protect against premature progression that would compromise genome integrity and viability.

Ref: Hinds & Weinberg, Cell Cycle Control by Cyclin E-CDK2, Curr Opin Cell Biol; Alberts et al., Chapter 17, G1/S Transition.

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