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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >MPS1-dependent mitotic BLM phosphorylation is important for chromosome stability
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MPS1-dependent mitotic BLM phosphorylation is important for chromosome stability

机译：MPS1依赖的有丝分裂BLM磷酸化对于染色体稳定性很重要

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摘要

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.
机译：纺锤体装配检查点（SAC）确保染色体与有丝分裂纺锤体的双极附着，并且对于忠实的染色体分离至关重要，从而防止了染色体不稳定（CIN）。遗传证据表明受损的SAC，CIN和癌症之间存在因果关系。布卢姆综合症（BS）是一种遗传疾病，易使受影响的个体患上癌症。 BS细胞显示出姊妹染色单体交换，染色体断裂和CIN的升高的速率。 BS基因产物BLM是RecQ解旋酶的成员，是维持基因组稳定性所需的。 BLM解旋酶与参与DNA复制，重组和修复的蛋白质相互作用，是修复停滞的复制叉和DNA损伤反应所必需的。在这里，我们目前的生化证据表明有丝分裂期间BLM磷酸化在维持染色体稳定性中的作用。 BLM与SAC激酶MPS1相关，并以MPS1依赖性方式在S144磷酸化。磷酸化的BLM与polo样激酶1（一种有丝分裂激酶）相互作用，该激酶通过其polo-box域（PBD）与磷酸丝氨酸/苏氨酸结合。此外，表达BLM-S144A的BS细胞显示正常水平的姐妹染色单体交换，但当SAC激活并不能显示广泛的染色体数目时，不能维持有丝分裂停滞。我们建议依赖MPS1的BLM磷酸化对于确保准确的染色体分离非常重要，其失调可能会导致癌症。

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