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#SAC

3 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

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) ensures that:

Cells delay anaphase until accurate chromosome alignment ensures equal segregation. Spindle assembly checkpoint implements this surveillance. Core machinery localizes to unattached kinetochores where scaffold KNL1 phosphorylated at MELT repeats by Mps1 kinase recruits Bub3-Bub1 and Bub3-BubR1 complexes. Bub1 phosphorylates histone H2A and Mad1, promoting catalytic platform where open Mad2 converts to closed Mad2 capable of trapping Cdc20. Mad2, BubR1 and Bub3 associate with Cdc20 forming diffusible Mitotic Checkpoint Complex that inhibits APC/C-Cdc20 by inserting BubR1 pseudosubstrate KEN boxe

Ref: Musacchio & Salmon, Spindle Assembly Checkpoint Molecular Mechanism, Nat Rev Mol Cell Biol 2007; Alberts, Chapter 17, SAC Signaling.

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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

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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