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#nuclear envelope breakdown

2 public questions tagged with this topic.

Cell Cycle Regulation

How do mitotic CDKs promote nuclear envelope breakdown?

Interphase nucleus bounded by double membrane supported by lamina composed of type V intermediate filaments lamin A/C, B1, B2 forming meshwork under inner nuclear membrane and linking to chromatin via emerin, LAP2 beta and LBR. Breakdown necessary for spindle access in metazoa relies on mitotic CDK1-Cyclin B catalyzed phosphorylation. CDK1 phosphorylates lamins at conserved sites flanking central alpha-helical rod: Ser22 and Ser392 on Lamin A/C cause electrostatic repulsion and disassembly of head-to-tail polymers into soluble dimers and tetramers. Concurrently CDK1 and Plk1 phosphorylate nucleoporins Nup98, Nup53, Nup93 triggering disassembly of nuclear pore complexes and release of importin beta-RanGTP gradients. Inner membrane proteins LBR and emerin phosphorylated dissociating from chromatin. This orchestrated cascade produces sequential fenestration near centrosomes then complete envelope collapse into endoplasmic reticulum network within minutes of prophase. At telophase, PP1 and PP2A dephosphorylate lamins, recruiting them to decondensing chromosomes via BAF protein for reassembly around daughter nuclei, re-establishing transport competence. 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: Guttinger et al., Mechanisms of Nuclear Envelope Breakdown and Reformation, Nat Rev Mol Cell Biol 2009; Alberts, Chapter 17.

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Cell Cycle Regulation

The mitotic CDK1-Cyclin B complex (MPF) is responsible for:

MPF converts interphase architecture into mitotic state through phosphorylation of hundreds of substrates. Nuclear entry of CDK1-Cyclin B, facilitated by phosphorylation of Cyclin B cytoplasmic retention sequence, allows access to chromatin proteins. Condensin I and II pentameric complexes containing SMC2, SMC4 become phosphorylated at non-SMC subunits CAP-D2, D3, CAP-G, H2, activating ATP-dependent loop extrusion that folds 10nm fiber into 700 nm wide rod chromosomes. Lamins phosphorylated at Ser22 Ser392 disassemble intermediate filament meshwork leading to nuclear envelope breakdown and merging with endoplasmic reticulum. Golgi matrix proteins GRASP65 GM130 phosphorylated causing vesiculation and partitioning. Interphase microtubule array destabilized while centrosomal gamma-TuRC recruitment of pericentrin enhanced drives bipolar spindle formation after Eg5 kinesin activation and NuMA dynein redistribution. Transcription inhibition through TFIIH and TFIID phosphorylation silences gene expression. Together these modifications reconfigure cell for chromosome capture, alignment and segregation, all attributable to single CDK1-Cyclin B holoenzyme activity rising at mitotic onset and falling after anaphase due to cyclin B destruction. 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: Hirano, Condensins and Mitotic Chromosome Architecture, Nat Rev Mol Cell Biol 2012; Alberts et al., Chapter 17, MPF Targets.

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