The spindle assembly checkpoint: More than just keeping track of the spindle

Abstract

Genome stability is essential for cell proliferation and survival. Consequently, genome integrity is monitored by two major checkpoints, the DNA damage response (DDR) and the spindle assembly checkpoint (SAC). The DDR monitors DNA lesions in G1, S, and G2 stages of the cell cycle and the SAC ensures proper chromosome segregation in M phase. There have been extensive studies characterizing the roles of these checkpoints in response to the processes for which they are named; however, emerging evidence suggests significant crosstalk between the checkpoints. Here we review recent findings demonstrating overlapping roles for the SAC and DDR in metaphase, and in response to DNA damage throughout the cell cycle.

Keywords: DNA damage; cell cycle; checkpoint; chromosome segregation; spindle assembly.

Figure 1

A) SAC is activated during metaphase by unattached kinetochores/spindle microtubules. The mitotic checkpoint complex (MCC) inhibits activation of the APC, which in turn prevents release of sister chromatid cohesion through securin/separase. B) Once all kinetochores are attached to the spindle, the MCC is disassembled and the APC is activated by CDC20, resulting in separase-dependent cleavage of cohesin and the onset of anaphase.

Figure 2

DDR activation after DNA damage where upstream kinases ATM and ATR recognize lesions and initiate signaling cascades for DNA repair.

Figure 3

Model for SAC and DDR integration in A) metaphase in response to both damaged DNA and spindle defects. Damaged DNA and uncapped telomeres can lead to SAC activation. In some cases, this is through ATM. ATM can also phosphorylate securin to induce arrest. In response to spindle defects, ATM and CHK1 phosphorylate a number of SAC components (red arrows) and are required for metaphase arrest. B) SAC components respond to DNA damage in interphase and are required for localization of damaged DNA to the nuclear periphery and efficient DNA repair. Additionally, SAC component BUB1 localizes to break sites and interacts with 53BP1 to promote NHEJ.