DREAM represses distinct targets by cooperating with different THAP domain proteins.

Csenge Gal,Julie Ahringer,Jane Murphy,Ni Huang,Alex Appert,Francesco Nicola Carelli,Chiara Cerrato,Yan Dong,Andrea Frapporti

doi:10.1016/j.celrep.2021.109835

Abstract

SummaryThe DREAM (dimerization partner [DP], retinoblastoma [Rb]-like, E2F, and MuvB) complex controls cellular quiescence by repressing cell-cycle and other genes, but its mechanism of action is unclear. Here, we demonstrate that two C. elegans THAP domain proteins, LIN-15B and LIN-36, co-localize with DREAM and function by different mechanisms for repression of distinct sets of targets. LIN-36 represses classical cell-cycle targets by promoting DREAM binding and gene body enrichment of H2A.Z, and we find that DREAM subunit EFL-1/E2F is specific for LIN-36 targets. In contrast, LIN-15B represses germline-specific targets in the soma by facilitating H3K9me2 promoter marking. We further find that LIN-36 and LIN-15B differently regulate DREAM binding. In humans, THAP proteins have been implicated in cell-cycle regulation by poorly understood mechanisms. We propose that THAP domain proteins are key mediators of Rb/DREAM function.

Highlights

During animal development, cell proliferation is tightly controlled, and differentiated cells spend the majority of the time in a quiescent, nondividing state
An RNAi screen identifies novel regulators of Rb/DREAM targets To identify proteins involved in DREAM transcriptional repression, we constructed a DREAM-regulated reporter gene by fusing the promoter of the target sep-1 to a histone-EGFP coding region and carried out an RNAi screen for genes
Using gene ontology (GO) analyses, we found that LIN-36-shared targets are highly enriched for cell-cycle and cell-division terms (Table S3)

Summary

Introduction

Cell proliferation is tightly controlled, and differentiated cells spend the majority of the time in a quiescent, nondividing state. The regulation of quiescence is crucial, as uncontrolled proliferation can lead to tumor formation, while premature senescence is associated with aging. The retinoblastoma (Rb) family of pocket proteins (Rb, p130, and p107) are key regulators of the cell-division cycle, regulating progression from G1 to S phase and maintaining the G0 state via transcriptional repression of proliferation-promoting genes (Dick and Rubin, 2013). The majority of cancers disable Rb protein function or alter its regulation (Liu et al, 2013; Nor Rashid et al, 2011; Sadasivam and DeCaprio, 2013). A mechanistic understanding of Rb proteins is essential for understanding their roles in normal development and cancerous transformations

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