The HDAC-Associated Sin3B Protein Represses DREAM Complex Targets and Cooperates with APC/C to Promote Quiescence

Abstract

SUMMARY The mammalian DREAM complex is responsible for the transcriptional repression of hundreds of cell-cycle-related genes in quiescence. How the DREAM complex recruits chromatin-modifying entities to aid in its repression remains unknown. Using unbiased proteomics analysis, we have uncovered a robust association between the chromatin-associated Sin3B protein and the DREAM complex. We have determined that genetic inactivation of Sin3B results in the de-repression of DREAM target genes during quiescence but is insufficient to allow quiescent cells to resume proliferation. However, inactivation of APC/CCDH1 was sufficient for Sin3B−/− cells, but not parental cells, to re-enter the cell cycle. These studies identify Sin3B as a transcriptional corepressor associated with the DREAM complex in quiescence and reveals a functional cooperation between E2F target repression and APC/CCDH1 in the negative regulation of cell-cycle progression.

The MuvB Complex Binds and Stabilizes Nucleosomes Downstream of the Transcription Start Site of Cell-Cycle Dependent Genes

“…histone tails and core, MuvB could prevent the unwrapping and movement of the +1 nucleosome. Although initial mass spectrometry analysis revealed few binding partners to human MuvB that could explain its repressive role, more recent studies have found MuvB can in certain contexts recruit proteins such as Sin3A (Bainor et al, 2018;Kim et al, 2021). Additional factors may also function to enhance repression in addition to the nucleosome binding activity of MuvB.…”

Cell cycle-independent integration of stress signals promotes Non-G1/G0 quiescence entry

“…The control of quiescence entry by cell cycle-independent integrators of stress stimuli could provide an adaptive advantage in environments with strong fluctuations of nutrients, as is the case for parasites with complex life cycles and cancer cells attempting metastasis (Wang et al, 2015). In mammalian cells, transcriptional repressors that could play an analogous role to Xbp1 are HES1 (Sueda et al, 2019, Coller, 2011 and the DREAM complex (Bainor et al, 2018, Miles and Breeden, 2017, Schade et al, 2019; however, it is unknown whether they can act as integrators of stress stimuli during quiescence entry. At least in prophase I mouse oocytes, it is clear that transcriptional repression by histone deacetylase-regulators akin to Xbp1 is essential to maintain a high-Cdk1 quiescent state (Wang et al, 2019).…”

Human DDK rescues stalled forks and counteracts checkpoint inhibition at unfired origins to complete DNA replication

“…synthesis or enter mitosis. As a complementary approach, we expressed and imaged the FUCCI sensor mKO2-Cdt1 (30-120) (Bainor et al, 2018;Sakaue-Sawano et al, 2008) and EGFP-PCNA in cells that had been synchronized by serum starvation and refed in the presence of 1-NM-PP1. The midpoint of Cdt1 degradation was used to identify the G1/S boundary, while PCNA foci were used to monitor DNA replication.…”