Rockefeller University uncovers dual cancer role of MLL4 protein

Researchers at Rockefeller University's Laboratory of Biochemistry and Molecular Biology used cryo‑EM imaging, genetics and in‑vitro transcription assays to produce the first complete structural model of the nine‑subunit MLL4 complex, revealing five subunits unique to MLL4 and a flexible arm that searches nucleosomes for histone tags. The study, published in *Molecular Cell*, shows that MLL4 acts as an oncogenic driver in certain leukemias, helping leukemia stem cells resist oxidative and genotoxic stress, while in solid tumours it cooperates with the tumor‑suppressor p53 to inhibit cancer growth. Knocking out MLL4 reduced activation of p53‑target genes involved in cell‑cycle arrest, DNA repair and apoptosis, indicating that MLL4 is essential for p53‑dependent transcription. "This research demonstrates that MLL4 has functions in transcription that were entirely unknown before," said senior author Robert Roeder. First author Jianfeng Sun added, "We also found that the N‑terminal region folds back onto the C‑terminal region to form a unique structural architecture essential for MLL4’s co‑activation function and for p53‑dependent transcription."