Dataset Information

Global transcriptomic changes of either cell cycle arrested parasites or cell cycle re-entered asexual P. falciparum 3D7 parasites.

ABSTRACT: Parasitic protists, including Plasmodium falciparum malaria parasites, evolved sophisticated biological features to adapt and survive in e.g. mosquito vectors and mammalian hosts. The parasite’s life cycle is extraordinarily controlled, oscillating between quiescent stages (e.g. sporozoites or gametocytes) and stages of intense proliferation. The atypical mode of asexual reproduction in erythrocytes (schizogony: asynchronous nuclear division in the absence of cytokinesis), is clearly divergent from cell division in higher eukaryotes but the mechanisms that control cell cycle progression are poorly understood. Here, depletion of exogenous factors was used to induce reversible cell cycle arrest and allowed transcriptomic investigations of cell cycle control mechanisms operating in the parasite. We show that in early stages of erythrocyte infection, parasites enter a quiescent, G0-like state due to implementation of a G1 restriction point prior to G1/S transition. This quiescence is reversible, with cells making a clear decision to re-engage the proliferation machinery in response to proliferation stimuli. Cell cycle arrest is an adaptive response rather than merely prolongation of the G1 phase, as demonstrated by a distinct transcriptome. The quiescence-proliferation decision-making process in malaria parasites has hallmarks of unique regulatory principles: quiescence is associated with a deregulation of the pre-replicative complex, underlined by transcriptional control of kinases, including PfPK5 as putative functional homologue of the master mammalian cell cycle regulator, CDK1. Cell cycle re-entry is highly coordinated and mediated by a set of early responsive transcripts involving NIMA and Aurora kinases, ApiAP2 transcription factors and calcium signaling. We therefore show that Apicomplexa are able to perform quiescence-proliferation decision-making in a highly coordinated fashion, using atypical cell cycle regulation machinery.

ORGANISM(S): Plasmodium falciparum

PROVIDER: GSE92289 | GEO | 2016/12/13

SECONDARY ACCESSION(S): PRJNA357102

REPOSITORIES: GEO

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Project description:Heldt2018 - Proliferation-quiescence decision in response to DNA damage This model is described in the article: A comprehensive model for the proliferation-quiescence decision in response to endogenous DNA damage in human cells. Heldt FS, Barr AR, Cooper S, Bakal C, Novák B. Proc. Natl. Acad. Sci. U.S.A. 2018 Feb; : Abstract: Human cells that suffer mild DNA damage can enter a reversible state of growth arrest known as quiescence. This decision to temporarily exit the cell cycle is essential to prevent the propagation of mutations, and most cancer cells harbor defects in the underlying control system. Here we present a mechanistic mathematical model to study the proliferation-quiescence decision in nontransformed human cells. We show that two bistable switches, the restriction point (RP) and the G1/S transition, mediate this decision by integrating DNA damage and mitogen signals. In particular, our data suggest that the cyclin-dependent kinase inhibitor p21 (Cip1/Waf1), which is expressed in response to DNA damage, promotes quiescence by blocking positive feedback loops that facilitate G1 progression downstream of serum stimulation. Intriguingly, cells exploit bistability in the RP to convert graded p21 and mitogen signals into an all-or-nothing cell-cycle response. The same mechanism creates a window of opportunity where G1 cells that have passed the RP can revert to quiescence if exposed to DNA damage. We present experimental evidence that cells gradually lose this ability to revert to quiescence as they progress through G1 and that the onset of rapid p21 degradation at the G1/S transition prevents this response altogether, insulating S phase from mild, endogenous DNA damage. Thus, two bistable switches conspire in the early cell cycle to provide both sensitivity and robustness to external stimuli. This model is hosted on BioModels Database and identified by: MODEL1703030000. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Barr2017 - Dynamics of p21 in hTert-RPE1 cells This deteministic model reveals that a bistable switch created by Cdt2, promotes irreversible S-phase entry by keeping p21 levels low, prevents premature S-phase exit upon DNA damage This model is described in the article: DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression. Barr AR, Cooper S, Heldt FS, Butera F, Stoy H, Mansfeld J, Novák B, Bakal C. Nat Commun 2017 Mar; 8: 14728 Abstract: Following DNA damage caused by exogenous sources, such as ionizing radiation, the tumour suppressor p53 mediates cell cycle arrest via expression of the CDK inhibitor, p21. However, the role of p21 in maintaining genomic stability in the absence of exogenous DNA-damaging agents is unclear. Here, using live single-cell measurements of p21 protein in proliferating cultures, we show that naturally occurring DNA damage incurred over S-phase causes p53-dependent accumulation of p21 during mother G2- and daughter G1-phases. High p21 levels mediate G1 arrest via CDK inhibition, yet lower levels have no impact on G1 progression, and the ubiquitin ligases CRL4Cdt2 and SCFSkp2 couple to degrade p21 prior to the G1/S transition. Mathematical modelling reveals that a bistable switch, created by CRL4Cdt2, promotes irreversible S-phase entry by keeping p21 levels low, preventing premature S-phase exit upon DNA damage. Thus, we characterize how p21 regulates the proliferation-quiescence decision to maintain genomic stability. This model is hosted on BioModels Database and identified by: BIOMD0000000660. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Dataset Information

Global transcriptomic changes of either cell cycle arrested parasites or cell cycle re-entered asexual P. falciparum 3D7 parasites.

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