Devaiah, B. N. | Search bioRxiv

bioRxiv2025

BRD4 regulates Aurora B kinase activity

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.

cell biology↗

bioRxiv2024

The ESCRT protein CHMP5 promotes T cell leukemia by controlling BRD4-p300-dependent transcription

Oncogene activity rewires cellular transcription, creating new transcription networks to which cancer cells become addicted, by mechanisms that are still poorly understood. Using human and mouse models of T cell acute lymphoblastic leukemia (T-ALL), we identify an essential nuclear role for CHMP5, a cytoplasmic endosomal sorting complex required for transport (ESCRT) protein, in establishing and maintaining the T-ALL transcriptional program. Nuclear CHMP5 promoted the T-ALL gene program by augmenting recruitment of the co-activator BRD4 by the histone acetyl transferase p300 selectively at enhancers and super-enhancers, an interaction that potentiated H3K27 acetylation at these regulatory enhancers. Consequently, loss of CHMP5 diminished BRD4 occupancy at enhancers and super-enhancers and impaired RNA polymerase II pause release, which resulted in downregulation of key T-ALL genes, notably MYC. Reinforcing its importance in T-ALL pathogenesis, CHMP5 deficiency mitigated chemoresistance in human T-ALL cells and abrogated T-ALL induction by oncogenic NOTCH1 in vivo. Thus, the ESCRT protein CHMP5 is an essential positive regulator of the transcriptional machinery promoting T-ALL disease. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/577409v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@191e10dorg.highwire.dtl.DTLVardef@4e5093org.highwire.dtl.DTLVardef@18c0a08org.highwire.dtl.DTLVardef@e6a887_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIIdentification of a nuclear role for the cytosolic ESCRT protein CHMP5 in transcription C_LIO_LICHMP5 mediates BRD4-dependent Pol II pause release and transcription of T-ALL genes C_LIO_LIP300-BRD4 induced enhancer and super-enhancer H3K27 acetylation requires CHMP5 C_LIO_LICHMP5 depletion mitigates chemoresistance and abrogates T-ALL initiation in vivo C_LI

cancer biology↗