Mitosis-specific MRN complex promotes a mitotic signaling cascade to regulate spindle dynamics and chromosome segregation
Mitosis-specific MRN complex promotes a mitotic signaling cascade to regulate spindle dynamics and chromosome segregation
复制标题
有丝分裂特异性 MRN 复合物促进有丝分裂信号级联，以调节纺锤体动力学和染色体分离。
DOI：
10.1073/pnas.1806665115
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发表时间：
2018-10-23
影响因子：
11.1
通讯作者：
Xu, Dongyi
中科院分区：
文献类型：
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作者：
Xu, Ran;Xu, Yixi;Xu, Dongyi
众所周知，MRE 11-RAD 50-NBS 1（MRN）复合物参与细胞周期所有阶段的DNA损伤反应途径。在这里，我们表明，MRN构成一个有丝分裂特异性的复合物，命名为mMRN，与蛋白质，MMAP。MMAP直接与MRE 11相互作用，并且是有丝分裂期间MRN复合物的最佳稳定性所必需的。MMAP与MRN在有丝分裂纺锤体中共定位，并且MMAP缺陷细胞显示与MRN缺陷细胞相似的异常纺锤体动力学和染色体分离。从机制上讲，MMAP和MRE 11都被有丝分裂激酶PLK 1过度磷酸化;磷酸化是组装mMRN复合物所必需的。组装的mMRN复合物使PLK 1能够与微管解聚酶KIF 2A相互作用并激活微管解聚酶KIF 2A，导致纺锤体周转和染色体分离。我们的研究确定了MRN复合物的有丝分裂特异性版本，其在PLK 1-KIF 2A信号级联中起作用以调节纺锤体动力学和染色体分布。
The MRE11-RAD50-NBS1 (MRN) complex is well known for participating in DNA damage response pathways in all phases of cell cycle. Here, we show that MRN constitutes a mitosis-specific complex, named mMRN, with a protein, MMAP. MMAP directly interacts with MRE11 and is required for optimal stability of the MRN complex during mitosis. MMAP colocalizes with MRN in mitotic spindles, and MMAP-deficient cells display abnormal spindle dynamics and chromosome segregation similar to MRN-deficient cells. Mechanistically, both MMAP and MRE11 are hyperphosphorylated by the mitotic kinase, PLK1; and the phosphorylation is required for assembly of the mMRN complex. The assembled mMRN complex enables PLK1 to interact with and activate the microtubule depolymerase, KIF2A, leading to spindle turnover and chromosome segregation. Our study identifies a mitosis-specific version of the MRN complex that acts in the PLK1-KIF2A signaling cascade to regulate spindle dynamics and chromosome distribution.