The Spindle Assembly Checkpoint: Clock or Domino?

Abstract

In each cell division, the newly duplicated chromosomes must be evenly distributed between the sister cells. Errors in this process during meiosis or mitosis are equally fatal: improper segregation of the chromosome 21 during human meiosis leads to Down syndrome (Conley, Aneuploidy: etiology and mechanisms, pp 1985), whereas in somatic cells, aneuploidy has been linked to carcinogenesis, by unbalancing the ratio of oncogenes and tumor suppressors (Holland and Cleveland, Nat Rev Mol Cell Biol 10(7): 478-487, 2009; Yuen et al., Curr Opin Cell Biol 17(6):576-582, 2005). Eukaryotic cells have developed a mechanism, known as the spindle assembly checkpoint, to detect erroneous attachment of chromosomes to the mitotic/meiotic spindle and delay the cell cycle to give enough time to resolve these defects. Research in the last 20 years, has demonstrated that the spindle assembly checkpoint is not only a pure checkpoint pathway, but plays a constitutive role in every cell cycle. Here, we review our current knowledge of how the spindle assembly checkpoint is integrated into the cell cycle machinery, and discuss some of the questions that have to be addressed in the future.

Cyclin B3 Is a Mitotic Cyclin that Promotes the Metaphase-Anaphase Transition

“…Work in tissue culture cells suggested a “wait-until-ready” model for the control of anaphase onset [1, 3], wherein unattached chromosomes activate the spindle assembly checkpoint (SAC) to prevent anaphase-promoting complex/cyclosome (APC/C) activation until all the chromosomes are attached (i.e., ready for anaphase). A shortcoming of this mechanism appears in a multinucleate cell where the first spindle to satisfy the SAC activates anaphase in the entire cell (Figure 1A) [12].…”

“…The spindle assembly checkpoint (SAC), whose reversal upon chromosome alignment is thought to time anaphase [1–3], is functional during the rapid mitotic cycles of the Drosophila embryo ; but its genetic inactivation had no consequence on the timing of the early mitoses. Mitotic cyclins—Cyclin A, Cyclin B, and Cyclin B3—influence mitotic progression and are degraded in a stereotyped sequence [4–11].…”

Overexpression of Fbxo6 inactivates spindle checkpoint by interacting with Mad2 and BubR1

“…Besides, more cell death was observed in HeLa flag-Fbxo6 cells, which reflects more severe mitotic catastrophe. Faithful chromosome segregation requires that each chromatid pair achieves bipolar attachment to the mitotic spindle before segregation [34,35]. Failure to attach to the spindle correctly before anaphase onset results in unequal chromosome segregation, which may lead to cell death or disease afterwards [36,37].…”

Ubiquitin‑like protein FAT10 regulates DNA damage repair via modification of proliferating cell nuclear antigen

“…Proliferating cell nuclear antigen (PCNA), a substrate identified in our previous study ( 10 ), is not only associated with DNA replication ( 11 ), but also with other fundamental cellular processes, such as chromatin remodeling, DNA repair, sister chromatid cohesion and cell cycle control ( 12 , 13 ). Dysregulation of DNA damage repair and signaling at cell cycle checkpoints is referred to as the DNA damage response (DDR) ( 14 ).…”