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Structural mechanism of Myb–MuvB assembly

Keelan Z. Guiley,A. Iness,S. Saini,S. Tripathi,J. Lipsick,Larisa Litovchick,S. M. Rubin

Published 2018 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance Myb family transcription factors are potent activators of cell proliferation and drivers of human cancer. B-Myb, the most ancient and conserved family member, induces transcription of mitotic genes. The MuvB complex, thought to be the master regulator of cell-cycle-dependent gene expression, is required for directing B-Myb to the proper promoters. We present a structural description of MuvB and how it recruits B-Myb. We identified a direct association between the B-Myb C-terminus and the MuvB components LIN9 and LIN52, and we determined the crystal structure of this subcomplex. Our data define LIN52 as a central transcription factor-binding hub in MuvB and reveal a Myb–MuvB interface that could be targeted with chemical inhibitors. The MuvB transcriptional regulatory complex, which controls cell-cycle-dependent gene expression, cooperates with B-Myb to activate genes required for the G2 and M phases of the cell cycle. We have identified the domain in B-Myb that is essential for the assembly of the Myb–MuvB (MMB) complex. We determined a crystal structure that reveals how this B-Myb domain binds MuvB through the adaptor protein LIN52 and the scaffold protein LIN9. The structure and biochemical analysis provide an understanding of how oncogenic B-Myb is recruited to regulate genes required for cell-cycle progression, and the MMB interface presents a potential therapeutic target to inhibit cancer cell proliferation.

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