DAB2IP maintains intestinal epithelial homeostasis by modulating the DNA replication stress response

Abstract The proliferative activity of undifferentiated cells in intestinal crypts is essential for maintaining intestinal homeostasis and facilitating regeneration in response to both pathophysiological conditions and stress. DAB2IP (Disabled homolog 2 interacting protein), a tumor suppressor, plays a crucial role in regulating various oncogenic pathways. Our previous study unveiled that DAB2IP serves as a cell cycle regulator by facilitating PLK1-mediated mitosis progression. In this study, we uncovered a novel DAB2IP function as it mediates the maintenance and regeneration of intestinal epithelial homeostasis in normal conditions and following irradiation (IR)-induced gastrointestinal (GI) injury. Mechanistically, we identified that DAB2IP interacts with the histone acetyltransferase HBO1 and promotes PLK1-mediated phosphorylation of HBO1. This phosphorylation event leads to HBO-directed lysine 14 acetylation on histone 3 (H3K14Ac), the loading of the minichromosome maintenance protein (MCM) complex onto chromatin, progression of DNA replication, and maintenance of genome integrity. Furthermore, we found that ATR regulates Cdk1-mediated phosphorylation of DAB2IP and that phosphorylation of DAB2IP is crucial for the formation and activation of the HBO1-PLK1 complex. Finally, ablating DAB2IP phosphorylation results in increased genomic instability due to incomplete replication of genomic DNA, as shown via the accumulation of anaphase ultrafine bridges and 53BP1 nuclear bodies in the G1 cell cycle phase. Collectively, our findings highlight the regulatory role of DAP2IP in DNA replication-an essential process for maintaining genomic stability and intestinal homeostasis.