A common strategy for initiating the transition from proliferation to quiescence

Abstract

Development, tissue renewal and long term survival of multi-cellular organisms is dependent upon the persistence of stem cells that are quiescent, but retain the capacity to re-enter the cell cycle to self-renew, or to produce progeny that can differentiate and re-populate the tissue. Deregulated release of these cells from the quiescent state, or preventing them from entering quiescence, results in uncontrolled proliferation and cancer. Conversely, loss of quiescent cells, or their failure to re-enter cell division, disrupts organ development and prevents tissue regeneration and repair. Understanding the quiescent state and how cells control the transitions in and out of this state is of fundamental importance. Investigations into the mechanics of G1 arrest during the transition to quiescence continue to identify striking parallels between the strategies used by yeast and mammals to regulate this transition. When cells commit to a stable but reversible arrest, the G1/S genes responsible for promoting S phase must be inhibited. This process, from yeast to humans, involves the formation of quiescence-specific complexes on their promoters. In higher cells these so-called DREAM complexes of E2F4/DP/RBL/MuvB recruit the highly conserved histone deacetylase HDAC1, which leads to local histone deacetylation and repression of S phase-promoting transcripts. Quiescent yeast cells also show pervasive histone deacetylation by the HDAC1 counterpart Rpd3. In addition, these cells contain quiescence-specific regulators of G1/S genes: Msa1 and Msa2, which can be considered components of the yeast equivalent of the DREAM complex. Despite a lack of physical similarities, the goals and the strategies used to achieve a reversible transition to quiescence are highly conserved. This motivates a detailed study of this process in the simple model organism: budding yeast.

The cell biology of quiescent yeast – a diversity of individual scenarios

“…At the molecular level, the retinoblastoma protein (Rb), a member of the so-called pocket protein family, and its interaction partners, the G1 cyclins and E2F transcription factor family, appear to be involved in quiescence establishment, but mutations that inactivate these cascades do not abolish quiescence entry in mice, flies and worms (Matson and Cook, 2017). In yeast, the Rb homologue Whi5, the histone deacetylase Rpd3, and the SCB binding factor (SBF)-binding proteins Msa1 and Msa2 have been shown to be involved in G1 arrest following nutrient starvation, but none of these factors are strictly required for quiescence survival (Miles and Breeden, 2016). Importantly, in both yeast and metazoans, an artificially prolonged arrest in G1 does not recapitulate the features of quiescence establishment (Martinez et al, 2004;Gasch et al, 2000;Radonjic et al, 2005;Coller et al, 2006).…”

“…This heterogeneity is markedly exemplified by muscle (Sutcu and Ricchetti, 2018;Tierney and Sacco, 2016) and hematopoietic (Nakamura-Ishizu et al, 2014) stem cells, in which transcriptome variations have been measured at the single-cell level (Yang et al, 2017;van Velthoven et al, 2017). Finally, even for a particular cell type under apparent homogeneous environmental conditions, such as clonal S. cerevisiae populations grown to stationary phase in liquid medium, non-proliferating cells display heterogeneous properties (Gray et al, 2004;Palková et al, 2014;Miles and Breeden, 2016;Laporte et al, 2011Laporte et al, , 2017Laporte et al, , 2018. Hence, the endless diversity of cells and habitats preclude the existence of a universal quiescence program.…”

Connecting virulence pathways to cell-cycle progression in the fungal pathogen Cryptococcus neoformans

“…In the recent C. neoformans publication, the cell-cycle network topology at G1/S phase was highlighted as a region of partial conservation between fungal species (Kelliher et al 2016 : Figure 6). In fact, the transcriptional machinery involved in the cellular “decision” to commit to the cell cycle, enter quiescence, or select another fate is functionally conserved in G1/S phase from S. cerevisiae to human cells (Miles and Breeden 2016 ). Further work is needed to understand interacting genes in pathogenic fungi and also in the conservation of these fungal and animal gene networks (Brown and Madhani 2012 ; Medina et al 2016 ).…”

Regulatory kinase genetic interaction profiles differ between environmental conditions and cellular states

“…Quiescence requires exit from the mitotic cell division cycle and initiation of a distinct G0 cell cycle phase, during which cells remain viable and maintain the capacity to re-initiate proliferative growth (Valcourt et al 2012) . In multicellular organisms development, tissue renewal and long term survival is dependent upon the persistence of stem cells that are quiescent, but retain the ability to re-enter the cell cycle to self-renew, or to produce progeny that can differentiate and re-populate the tissue (Miles and Breeden 2017) . Exit from quiescence, and initiation of aberrant proliferation, is a hallmark of cancer (Hanahan and Weinberg 2011;Miles and Breeden 2017) .…”

“…In multicellular organisms development, tissue renewal and long term survival is dependent upon the persistence of stem cells that are quiescent, but retain the ability to re-enter the cell cycle to self-renew, or to produce progeny that can differentiate and re-populate the tissue (Miles and Breeden 2017) . Exit from quiescence, and initiation of aberrant proliferation, is a hallmark of cancer (Hanahan and Weinberg 2011;Miles and Breeden 2017) . Conversely, many cancer-related deaths are the result of quiescent tumor cells that are resistant to therapeutics and underlie tumor recurrence (Yano et al 2017;Borst 2012) .…”