# Recruitment of BRD4 to the ASXL1 genomic targets depends on the extra-terminal domain of BRD4

## TL;DR

This study explains how the protein ASXL1 interacts with BRD4 in cancer cells, revealing a key mechanism behind their strong genetic link.

## Contribution

The study identifies the structural and molecular basis for the ASXL1-BRD4 interaction and its role in cancer.

## Key findings

- ASXL1 and BRD4 form a tight complex through the extraterminal domain of BRD4.
- Truncated ASXL1 variants retain BRD4 binding, with one variant showing enhanced recruitment ability.
- ASXL1 and BRD4 show a strong positive relationship in multiple cancer types.

## Abstract

ASXL1 is a well-established driver of a wide range of cancers. Here, we identify a high level of genetic correlation between ASXL1 and the major transcriptional activator BRD4 in cancer cells and characterize the molecular mechanism underlying this correlation. Structural and biochemical data show the formation of a tight complex between the extraterminal domain of BRD4 and the BRD4-binding motif of ASXL1. ChIP-seq analysis of mutated ASXL1 that cannot bind BRD4 demonstrates that the recruitment of BRD4 to the ASXL1 genomic targets depends on this interaction. We find that the cancer-related truncated variants comprising residues 1-645 and 1-591 of ASXL1 (ASXL11-645 and ASXL11-591) retain BRD4 binding function, with ASXL11-645 showing an enhanced ability to recruit BRD4 to promoters of ASXL1 target genes. In contrast to ASXL11-591, ASXL11-645 simultaneously and independently interacts with BRD4 and the H3K4-specific methyltransferases MLL3/4, whereas the shorter variant is lacking the MLL3/4-binding site and interacts only with BRD4. Genomic data from six cancer types reveals a strong positive ASXL1-BRD4 relationship, with BRD4 occupying the ASXL1 promoter and thus pointing to a possible feed-forward mechanism. Our findings provide mechanistic details by which ASXL1 associates with BRD4 and shed light on the biological significance of this association.

ASXL1 is often mutated in myeloid cancers. Here, the authors describe the molecular and structural mechanism by which ASXL1 associates with the transcriptional coactivator BRD4, helping to explain their high correlation in cancers.