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#chromosome alignment

9 public questions tagged with this topic.

Cytoskeleton

During mitosis, kinetochore microtubules:

Kinetochore microtubule fibers K fibers dynamic behavior changes across mitotic stages governed by tension sensing checkpoint signaling and motor forces generating chromosome movement. During prometaphase microtubules nucleated at centrosomal poles probe cytoplasm via dynamic instability growth at plus end at several microns per minute capture kinetochore through NDC80 complex forming bundles of 20 to 40 microtubules stabilized by CLASP and formins. Until anaphase kinetochore microtubules continue polymerization at plus end while minus ends depolymerize at poleward flux mediated by kinesin-13 and katanin maintaining tension across sister chromatids bi oriented at metaphase plate. This tension stabilizes attachments via Aurora B spatial separation and silences spindle assembly checkpoint via removal of Mad2 BubR1. At anaphase onset after separase cleaves cohesin switch to coordinated depolymerization at both ends: plus end depolymerizes at kinetochore Pacman mechanism driven by kinesin-13 and Dam1 ring, minus end at pole, pulling chromosomes poleward segregation of genetic material without continuous growth throughout mitosis. Continuous growth not observed switch essential.

Ref: Cheeseman & Desai, Annu Rev Cell Dev Biol – Kinetochore microtubules polymerize until anaphase then depolymerize.

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Cell Division

Which phase of mitosis is characterized by alignment of chromosomes at the metaphase plate?

Metaphase defined by alignment of condensed chromosomes along equatorial plate equidistant between spindle poles is visually hallmark of mitosis used for karyotyping. Following prometaphase, chromosomes undergo congression driven by opposing forces: CENP-E plus-end-directed kinesin transporting chromosomes toward plate, and dynein mediated poleward force, plus dynamic instability of microtubules causing oscillations. Correct amphitelic attachment where sister kinetochores bind microtubule bundles emanating from opposite centrosomes generates tension across centromere stretching inter-kinetochore distance, satisfying checkpoint. Erroneous syntelic or merotelic attachments lacking tension are destabilized by Aurora B kinase concentrated at inner centromere phosphorylating Ndc80 and KNL1 reducing microtubule affinity, giving second chance for proper biorientation. When all chromosomes aligned, metaphase plate forms, cyclin B-CDK1 activity remains maximal maintaining condensin activity and securin stability, and spindle assembly checkpoint silences awaiting anaphase trigger, ensuring synchronous segregation for equal genome distribution. This circuitry is highly conserved across eukaryotes, integrating growth factor signals, DNA damage surveillance, and developmental cues, and its disruption frequently underlies oncogenesis, providing targets for checkpoint inhibitors and cancer therapeutics.

Ref: Alberts et al., Molecular Biology of the Cell, 7th ed., Chapter 17, Metaphase Alignment Mechanisms.

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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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