The histone acetyltransferase (HAT) KAT7/HBO1/MYST2 plays a crucial role in the pre-replication complex (pre-RC) formation, DNA replication and cell proliferation via acetylation of histone H4 and H3. In a search for protein kinase D1 (PKD1)-interacting proteins, we have identified KAT7 as a potential PKD1 substrate. We show that PKD1 directly interacts and phosphorylates KAT7 at Thr97 and Thr331 in vitro and in vivo. PKD1-mediated phosphorylation of KAT7 enhances its expression levels and stability by reducing its ubiquitination-mediated degradation. Significantly, the phospho-defective mutant KAT7-Thr97/331A attenuates histone H4 acetylation levels, MCM2/6 loading on the chromatin, DNA replication and cell proliferation. Similarly, PKD1 knockdown decreases, whereas the constitutive active mutant PKD1-CA increases histone H4 acetylation levels and MCM2/6 loading on the chromatin. Overall, these results suggest that PKD1-mediated phosphorylation of KAT7 may be required for pre-RC formation and DNA replication.

组蛋白乙酰转移酶 (HAT) KAT7/HBO1/MYST2 通过组蛋白 H4 和 H3 的乙酰化在复制前复合物 (pre-RC) 形成、DNA 复制和细胞增殖中发挥至关重要的作用。在寻找蛋白激酶 D1 (PKD1) 相互作用蛋白时，我们发现 KAT7 是潜在的 PKD1 底物。我们发现 PKD1 在体外和体内直接与 KAT7 的 Thr97 和 Thr331 相互作用并磷酸化。PKD1 介导的 KAT7 磷酸化通过减少泛素化介导的降解来增强其表达水平和稳定性。值得注意的是，磷酸化缺陷突变体 KAT7-Thr97/331A 会减弱组蛋白 H4 乙酰化水平、染色质上的 MCM2/6 负载、DNA 复制和细胞增殖。同样，PKD1 敲低减少，而组成型活性突变体 PKD1-CA 增加组蛋白 H4 乙酰化水平和染色质上的 MCM2/6 负载。总的来说，这些结果表明 PKD1 介导的 KAT7 磷酸化可能是前 RC 形成和 DNA 复制所必需的。