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#Spindle Assembly Checkpoint

5 public questions tagged with this topic.

Cell Cycle Regulation

What is the role of the Spindle Assembly Checkpoint (SAC)?

Chromosome missegregation produces aneuploidy implicated in tumorigenesis, congenital disorders, and embryonic lethality, necessitating surveillance by spindle assembly checkpoint. Sensor is kinetochore assembled on CENP-A containing centromeric nucleosomes that binds microtubule plus ends via Ndc80 complex. Unattached kinetochores act as catalytic platforms where Mad1-Mad2 heterotetramer converts soluble open Mad2 into closed conformation that binds Cdc20. Together with BubR1, Bub3, and Bub1 phosphorylated by Mps1 kinase, they generate diffusible mitotic checkpoint complex that inhibits APC/C-Cdc20 throughout cytoplasm, blocking ubiquitination of securin and cyclin B. Aurora B kinase at inner centromere destabilizes low-tension syntelic or merotelic attachments by phosphorylating Ndc80, creating unattached kinetochores that re-engage checkpoint. Upon biorientation with sister kinetochores attached to opposite poles under tension, Mad1-Mad2 recruitment ceases, checkpoint complex disassembles, APC/C activates, and synchronous anaphase proceeds, ensuring 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: Musacchio, Current Biology 2015, SAC Mechanism. Alberts 7th ed., Chapter 17, Mitosis Quality.

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Cell Cycle Regulation

The Spindle Assembly Checkpoint (SAC) monitors:

Spindle assembly checkpoint, also termed mitotic checkpoint, monitors mechanical and attachment state of chromosomes to ensure faithful segregation. Key parameter sensed is not DNA sequence integrity but physical connection between centromeric region, specifically kinetochore proteinaceous plaque assembled on centromeric chromatin, and dynamic microtubule plus ends emanating from spindle poles. Unattached kinetochores catalyze formation of diffusible inhibitor MCC that blocks APC/C-Cdc20, delaying anaphase until all sister pairs are bi-oriented with kinetochores attached to opposite poles and under tension from depolymerizing microtubules exerting pulling forces. Attachment is detected through Mps1 kinase sensing Ndc80-microtubule engagement and through tension-dependent dephosphorylation by PP1 phosphatase recruited to KNL1. DNA damage repair is surveyed by ATM/ATR kinases acting in interphase, G1-S transition is controlled by Rb-E2F pathway integrating growth signals, centrosome duplication is licensed by Plk4 and separase. Therefore SAC specifically ensures every chromosome is properly hooked to spindle apparatus, preventing chromosome loss or gain that underlies aneuploidy, tumor evolution, and developmental disorders when checkpoint fails.

Ref: Musacchio & Salmon, Nature Rev Mol Cell Biol 2007, Spindle Checkpoint Mechanics; Foley & Kapoor, Nature Rev Mol Cell Biol 2013, Kinetochore Attachment.

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