The DREAM complex through its subunit Lin37 cooperates with Rb to initiate quiescence.

Christina Fs Mages,Stephan H Bernhart,Gerd A Müller,Axel Wintsche

doi:10.7554/elife.26876

Abstract

The retinoblastoma Rb protein is an important factor controlling the cell cycle. Yet, mammalian cells carrying Rb deletions are still able to arrest under growth-limiting conditions. The Rb-related proteins p107 and p130, which are components of the DREAM complex, had been suggested to be responsible for a continued ability to arrest by inhibiting E2f activity and by recruiting chromatin-modifying enzymes. Here, we show that p130 and p107 are not sufficient for DREAM-dependent repression. We identify the MuvB protein Lin37 as an essential factor for DREAM function. Cells not expressing Lin37 proliferate normally, but DREAM completely loses its ability to repress genes in G0/G1 while all remaining subunits, including p130/p107, still bind to target gene promoters. Furthermore, cells lacking both Rb and Lin37 are incapable of exiting the cell cycle. Thus, Lin37 is an essential component of DREAM that cooperates with Rb to induce quiescence.

Highlights

The retinoblastoma protein Rb regulates cell cycle-dependent gene expression and is mutated in many cancer types (Hanahan and Weinberg, 2000)
Rb preferentially interacts with E2f1-3, and p130/p107 mainly bind to E2f4/5 (Helin et al, 1992; Lees et al, 1993; Liban et al, 2017). p107 or p130 are components of the DREAM complex (Guiley et al, 2015; Litovchick et al, 2007; Pilkinton et al, 2007; Schmit et al, 2007)
Three small conserved regions in the central part of the protein could be identified: a potential nuclear localization signal (NLS) and two adjacent conserved domains (CD1 and CD2) that are separated by a spacer of eight weakly conserved amino acids

Summary

Introduction

The retinoblastoma protein Rb regulates cell cycle-dependent gene expression and is mutated in many cancer types (Hanahan and Weinberg, 2000). All of them interact with E2f proteins to form complexes that repress expression of genes necessary for cell cycle progression in G0 and early G1 (Classon and Dyson, 2001; Classon and Harlow, 2002; Cobrinik, 2005; Dick and Rubin, 2013; Burkhart and Sage, 2008). While DREAM binds and represses cell cycle genes with maximal expression in S, G2, and M phases through E2F and CHR promoter elements, E2f-Rb complexes cannot bind to CHR sites. They can interact with E2F binding sites of S phase genes (Litovchick et al, 2007; Hurford et al, 1997; Muller et al, 2014; Muller et al, 2016). Rb and p130/p107 have overlapping, and clearly distinct functions in the repression of cell cycle genes

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