Ibrahim Bashar, Henze Richard
Al-Qunfudah University College, Umm Al-Qura University, 1109 Makkah Al-Mukarramah, Saudi Arabia.
Bio Systems Analysis Group, Institute of Computer Science, Jena Center for Bioinformatics and Friedrich Schiller University, 07743 Jena, Germany.
Int J Mol Sci. 2014 Oct 21;15(10):19074-91. doi: 10.3390/ijms151019074.
To guarantee genomic integrity and viability, the cell must ensure proper distribution of the replicated chromosomes among the two daughter cells in mitosis.The mitotic spindle assembly checkpoint (SAC) is a central regulatory mechanism to achieve this goal. A dysfunction of this checkpoint may lead to aneuploidy and likely contributes to the development of cancer. Kinetochores of unattached or misaligned chromosomes are thought to generate a diffusible ''wait-anaphase'' signal, which is the basis for downstream events to inhibit the anaphase promoting complex/cyclosome (APC/C). The rate of Cdc20:C-Mad2 complex formation at the kinetochore is a key regulatory factor in the context of APC/C inhibition. Computer simulations of a quantitative SAC model show that the formation of Cdc20:C-Mad2 is too slow for checkpoint maintenance when cytosolic O-Mad2 has to encounter kinetochores by diffusion alone. Here, we show that an active transport of O-Mad2 towards the spindle mid-zone increases the efficiency of Mad2-activation. Our data indicate that this mechanism can greatly enhance the formation of Cdc20:Mad2 and furthermore gives an explanation on how the ''wait-anaphase'' signal can dissolve abruptly within a short time. Our results help to understand parts of the SAC mechanism that remain unclear.
为确保基因组的完整性和细胞活力，细胞必须在有丝分裂过程中确保复制后的染色体在两个子细胞之间正确分配。有丝分裂纺锤体组装检查点（SAC）是实现这一目标的核心调控机制。该检查点功能失调可能导致非整倍体，并可能促进癌症的发展。未附着或排列错误的染色体的动粒被认为会产生一种可扩散的“等待后期”信号，这是下游事件抑制后期促进复合物/细胞周期体（APC/C）的基础。在动粒处Cdc20:C-Mad2复合物的形成速率是APC/C抑制背景下的关键调控因子。定量SAC模型的计算机模拟表明，当胞质O-Mad2仅通过扩散与动粒相遇时，Cdc20:C-Mad2的形成速度过慢，无法维持检查点。在此，我们表明O-Mad2向纺锤体中区的主动运输提高了Mad2激活的效率。我们的数据表明，这种机制可以极大地增强Cdc20:Mad2的形成，并进一步解释了“等待后期”信号如何在短时间内突然消失。我们的结果有助于理解SAC机制中尚不清楚的部分。
