Structure and function of MuvB complexes

Abstract

Proper progression through the cell-division cycle is critical to normal development and homeostasis and is necessarily misregulated in cancer. The key to cell-cycle regulation is the control of two waves of transcription that occur at the onset of DNA replication (S phase) and mitosis (M phase). MuvB complexes play a central role in the regulation of these genes. When cells are not actively dividing, the MuvB complex DREAM represses G1/S and G2/M genes. Remarkably, MuvB also forms activator complexes together with the oncogenic transcription factors B-MYB and FOXM1 that are required for the expression of the mitotic genes in G2/M. Despite this essential role in the control of cell division and the relationship to cancer, it has been unclear how MuvB complexes inhibit and stimulate gene expression. Here we review recent discoveries of MuvB structure and molecular interactions, including with nucleosomes and other chromatin-binding proteins, which have led to the first mechanistic models for the biochemical function of MuvB complexes.

Fig. 1:. Regulation of cell-cycle gene expression by MuvB and RB-E2F complexes.

Two sets of genes are maximally expressed in either G1 and S phases (G1/S genes), or in G2 and mitosis (G2/M genes). Central features that discriminate both gene sets are E2F promoter elements in G1/S genes and CHR promoter sites in G2/M genes. The MuvB complex (pink) regulates expression of these genes with other proteins that act as repressors (red) and activators (green) of transcription. The DREAM complex can bind and repress both sets in G0 and early G1 through the interaction of E2F4/5-DP with E2F promoter elements, and of the MuvB component LIN54 with CHR sites, respectively. RB together with the activator E2Fs (E2F1–3a) also bind and repress G1/S genes by contacting E2F promoter sites. When cells enter the cell cycle from G0, CDK-cyclin complexes are activated and phosphorylate RB, p107, and p130, resulting in the disruption of the repressive DREAM and RB-E2F complexes. Expression of G1/S genes is stimulated in late G1 by activator E2Fs that remain bound to E2F sites, with peak expression occurring in S phase. At the end of S phase, activator E2Fs are degraded, and G1/S genes are repressed by the non-canonical E2F7/8. One cell cycle-regulator encoded by a G1/S gene is the transcription factor B-MYB. B-MYB binds to MuvB to form the MMB complex. This interaction is essential to recruit FOXM1 (MMB-FOXM1). In G2/M, B-MYB is degraded, and maximum expression of genes coincides with binding of the FOXM1-MuvB complex to CHR elements in promoters. Examples of G1/S or G2/M genes that encode for prominent cell-cycle regulatory proteins are given in the grey boxes.

Fig. 2:. MuvB structure.

(A) MuvB domain architecture and known domain structures. The PDB codes are 6C48 (LIN9^MybBD-LIN9^MybBD-B-Myb), 7N40 (MuvB^N), and 5FD3 (LIN54^DBD). (B) Overall model for atomic resolution structure generated by aligning known domain structures with structural predictions from AlphaFold. Regions of predicted disorder are shown with a surface representation only.

Fig. 3:. Model for MuvB function in repression and activation of cell-cycle genes.

DREAM-mediated gene repression occurs in G0 and early G1. MuvB forms a repressive complex near the transcription start site (TSS) with p130/p107, E2F4/5, and DP proteins facilitated by LIN52 phosphorylation by DYRK1A. Through MuvBN, MuvB binds and stabilizes the +1 nucleosome of target gene promoters and may recruit co-repressors and inhibit the activity of co-activators required for gene transcription. In G2/M the sequential binding of B-MYB and later FOXM1 to the MuvB core forms activator MuvB complexes which may prevent binding to the +1 nucleosome, inhibit the activity of co-repressors, and recruit factors that promote gene transcription.