Faithful chromosome segregation maintains chromosomal stability as errors in this process contribute to chromosomal instability (CIN) which has been observed in many diseases including cancer. Epigenetic regulation of kinetochore proteins such as Cse4 (CENP-A in humans) plays a critical role in high fidelity chromosome segregation. Here we show that Cse4 is a substrate of evolutionarily conserved Cdc7 kinase, and that Cdc7-mediated phosphorylation of Cse4 prevents CIN. We determined that Cdc7 phosphorylates Cse4 in vitro and interacts with Cse4 in vivo in a cell cycle dependent manner. Cdc7 is required for kinetochore integrity as reduced levels of CEN-associated Cse4, a faster exchange of Cse4 at the metaphase kinetochores and defects in chromosome segregation are observed in a cdc7-7 strain. Phosphorylation of Cse4 by Cdc7 is important for cell survival as constitutive association of a kinase dead variant of Cdc7 (cdc7-kd) with Cse4 at the kinetochore leads to growth defects. Moreover, phosphodeficient mutations of Cse4 for consensus Cdc7 target sites contribute to CIN phenotype. In summary, our results have defined a role for Cdc7-mediated phosphorylation of Cse4 in faithful chromosome segregation.

忠实的染色体分离可维持染色体稳定性，因为此过程中的错误会导致染色体不稳定性 (CIN)，这已在包括癌症在内的许多疾病中观察到。着丝粒蛋白如 Cse4（人类 CENP-A）的表观遗传调控在高保真染色体分离中起着关键作用。在这里，我们表明 Cse4 是进化上保守的 Cdc7 激酶的底物，并且 Cdc7 介导的 Cse4 磷酸化可防止 CIN。我们确定 Cdc7 在体外磷酸化 Cse4 并在体内以细胞周期依赖性方式与 Cse4 相互作用。Cdc7 是动粒完整性所必需的，因为CEN相关的 Cse4 水平降低，在cdc7-7中观察到中期动粒处 Cse4 的更快交换和染色体分离缺陷拉紧。Cdc7 对 Cse4 的磷酸化对于细胞存活很重要，因为 Cdc7 ( cdc7-kd ) 激酶死亡变体与着丝粒处的 Cse4 的组成性关联会导致生长缺陷。此外，Cse4 的共同 Cdc7 靶位点的磷酸化缺陷突变有助于 CIN 表型。总之，我们的结果确定了 Cdc7 介导的 Cse4 磷酸化在忠实染色体分离中的作用。