BRD4 regulates Aurora B kinase activity

Abstract

BRD4, a pleiotropic regulator of chromatin structure and transcription, plays critical roles in cancer and immune responses. Unlike other transcriptional regulators, BRD4 largely remains bound to chromosomes during early mitosis. Here we report that BRD4 also regulates mitosis through its direct interaction with and phosphorylation of Aurora B kinase, an essential regulator of mitosis. BRD4 binding to Aurora B inhibits its kinase activity, preventing autophosphorylation and phosphorylation of the key mitotic targets histone H3 and MCAK, the mitotic centromere associated kinesin. This inhibition is relieved during metaphase when JNK is activated and phosphorylates BRD4, triggering its transient release from chromatin. Importantly, Aurora B activity during mitosis inversely correlates with BRD4 binding and directly correlates with JNK activation and BRD4 release. Our findings thus reveal a regulatory mechanism whereby Aurora B activity is directly controlled by BRD4, which in turn is regulated by JNK. Significance StatementBRD4 has been extensively characterized for its role in regulating chromatin structure and transcription. But its function during mitosis has remained unclear. This study reveals a novel mechanism by which BRD4 directly regulates mitotic progression through its interaction with and inhibition of Aurora B kinase, a central player in chromosome segregation. The timely release of BRD4 from chromatin via JNK-mediated phosphorylation enables Aurora B activation at a critical stage of mitosis. These findings uncover a previously unrecognized BRD4-Aurora B-JNK signaling axis that integrates chromatin dynamics with mitotic control, offering new insights into cell cycle regulation and potential therapeutic targets in cancer.