MPS1-dependent mitotic BLM phosphorylation is important for chromosome stability
MPS1-dependent mitotic BLM phosphorylation is important for chromosome stability
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DOI：
10.1073/pnas.0601828103
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发表时间：
2006-08-01
影响因子：
11.1
通讯作者：
Wang, Yi
中科院分区：
文献类型：
--
作者：
Leng, Mei;Chan, Doug W.;Wang, Yi
纺锤体组装检查点（SAC）确保染色体双极附着到有丝分裂纺锤体上，并且对于忠实的染色体分离至关重要，从而防止染色体不稳定性（CIN）。遗传学证据表明SAC受损、CIN和癌症之间存在因果关系。布卢姆综合征（BS）是一种遗传性疾病，易使受影响的个体患癌症。BS细胞姐妹染色单体交换、染色体断裂和CIN的发生率升高。BS基因产物BLM是维持基因组稳定性所需的RecQ解旋酶的成员。BLM解旋酶与参与DNA复制、重组和修复的蛋白质相互作用，并且是修复停滞复制叉和DNA损伤反应所需的。在这里，我们提出的生化证据表明，在有丝分裂过程中的BLM磷酸化在维持染色体稳定性的作用。BLM与SAC激酶MPS 1相关，并以MPS 1依赖性方式在S144处磷酸化。磷酸化BLM与polo样激酶1相互作用，polo样激酶1是一种通过polo盒结构域（PBD）与磷酸丝氨酸/苏氨酸结合的有丝分裂激酶。此外，表达BLM-S144 A的BS细胞显示正常水平的姐妹染色单体交换，但当SAC被激活时不能维持有丝分裂停滞，并显示染色体数目的广泛分布。我们认为MPS 1依赖的BLM磷酸化对于确保准确的染色体分离是重要的，其失调可能导致癌症。
Spindle assembly checkpoint (SAC) ensures bipolar attachment of chromosomes to the mitotic spindle and is essential for faithful chromosome segregation, thereby preventing chromosome instability (CIN). Genetic evidence suggests a causal link between compromised SAC, CIN, and cancer. Bloom syndrome (BS) is a genetic disorder that predisposes affected individuals to cancer. BS cells exhibit elevated rates of sister chromatid exchange, chromosome breaks, and CIN. The BS gene product, BLM, is a member of the RecQ helicases that are required for maintenance of genome stability. The BLM helicase interacts with proteins involved in DNA replication, recombination, and repair and is required for the repair of stalled-replication forks and in the DNA damage response. Here we present biochemical evidence to suggest a role of BLM phosphorylation during mitosis in maintaining chromosome stability. BLM is associated with the SAC kinase MPS1 and is phosphorylated at S144 in a MPS1-dependent manner. Phosphorylated BLM interacts with polo-like kinase 1, a mitotic kinase that binds to phosphoserine/threonine through its polo-box domain (PBD). Furthermore, BS cells expressing BLM-S144A show normal levels of sister chromatid exchange but fail to maintain the mitotic arrest when SAC is activated and exhibit a broad distribution of chromosome numbers. We propose that MPS1-dependent BLM phosphorylation is important for ensuring accurate chromosome segregation, and its deregulation may contribute to cancer.