Nuclear DAB2IP regulates DNA replication initiation through activating PLK1-mediated HBO1 phosphorylation

DAB2IP (Disabled homolog 2 interacting protein), a recognized tumor suppressor, plays a pivotal role in regulating various oncogenic pathways. Our previous research demonstrated that DAB2IP functions as a cell cycle regulator by facilitating PLK1-mediated mitosis progression. Here, we elucidate a novel function of DAB2IP in promoting DNA replication origin firing. Mechanistically, we identified that DAB2IP localizes to the nucleus, where it interacts with the histone acetyltransferase HBO1 and enhances the HBO1-PLK1 interaction. DAB2IP facilitates PLK1-mediated phosphorylation of HBO1, which subsequently promotes HBO1-directed acetylation of histone 3 at lysine 14 (H3K14Ac). This modification enables the loading of the minichromosome maintenance protein (MCM) complex onto chromatin, thereby supporting DNA replication and maintaining genome integrity. Additionally, we found that ATR regulates CDK1-mediated phosphorylation of DAB2IP, and that this phosphorylation is essential for the formation and activation of the HBO1-PLK1 complex. Ablation of DAB2IP phosphorylation results in increased genomic instability due to incomplete replication of genomic DNA, as evidenced by the accumulation of anaphase ultrafine bridges and 53BP1 nuclear bodies in G1 phase of the cell cycle. In summary, our findings underscore the critical regulatory role of DAB2IP in DNA replication initiation and genomic stability maintenance, providing new insights into its function in cellular homeostasis.