Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States.
Elife. 2020 Jun 1;9:e55096. doi: 10.7554/eLife.55096.
During mitosis, the Spindle Assembly Checkpoint (SAC) maintains genome stability while also ensuring timely anaphase onset. To maintain genome stability, the SAC must be strong to delay anaphase even if just one chromosome is unattached, but for timely anaphase onset, it must promptly respond to silencing mechanisms. How the SAC meets these potentially antagonistic requirements is unclear. Here we show that the balance between SAC strength and responsiveness is determined by the number of 'MELT' motifs in the kinetochore protein Spc105/KNL1 and their Bub3-Bub1 binding affinities. Many strong MELT motifs per Spc105/KNL1 minimize chromosome missegregation, but too many delay anaphase onset. We demonstrate this by constructing a Spc105 variant that trades SAC responsiveness for much more accurate chromosome segregation. We propose that the necessity of balancing SAC strength and responsiveness drives the dual evolutionary trend of the amplification of MELT motif number, but degeneration of their functionally optimal amino acid sequence.
在有丝分裂过程中，纺锤体组装检查点（SAC）在确保及时进入后期的同时维持基因组稳定性。为了维持基因组稳定性，SAC 必须足够强大，即使只有一条染色体未附着，也要延迟后期，但为了及时进入后期，它必须迅速响应沉默机制。SAC 如何满足这些潜在的拮抗需求尚不清楚。在这里，我们表明 SAC 强度和响应能力之间的平衡取决于动粒蛋白 Spc105/KNL1 中的“MELT”基序数量及其与 Bub3-Bub1 的结合亲和力。每个 Spc105/KNL1 中存在许多强 MELT 基序可以最大程度地减少染色体错误分离，但过多的 MELT 基序会延迟后期的开始。我们通过构建 Spc105 变体来证明这一点，该变体可以交换 SAC 的响应能力，从而实现更准确的染色体分离。我们提出，平衡 SAC 强度和响应能力的必要性推动了 MELT 基序数量的双重进化趋势，但它们的功能最佳氨基酸序列却退化了。
