PCNA-Mediated Degradation of p21 Coordinates the DNA Damage Response and Cell Cycle Regulation in Individual Cells

Cells need to preserve genome integrity despite varying cellular and physical states. p53, the guardian of the genome, plays a crucial role in the cellular response to DNA damage by triggering cell cycle arrest, apoptosis or senescence. Mutations in p53 or alterations in its regulatory network are major driving forces in tumorigenesis. As multiple studies indicate beneficial effects for hyperthermic treatments during radiation-or chemotherapy of human cancers, we aimed to understand how p53 dynamics after genotoxic stress are modulated by changes in temperature across a physiological relevant range. To this end, we employed a combination of time-resolved live-cell microscopy and computational analysis techniques to characterise the p53 response in thousands of individual cells. Our results demonstrate that p53 dynamics upon ionizing radiation are temperature dependent. In the range of 33 °C to 39 °C, pulsatile p53 dynamics are modulated in their frequency. Above 40 °C, which corresponds to mild hyperthermia in a clinical setting, we observed a reversible phase transition towards sustained hyperaccumulation of p53 disrupting its canonical response to DNA double strand breaks. Moreover, we provide evidence that mild hyperthermia alone is sufficient to induce a p53 response in the absence of genotoxic stress. These insights highlight how the p53-mediated DNA damage response is affected by alterations in the physical state of a cell and how this can be exploited by appropriate timing of combination therapies to increase the efficiency of cancer treatments.

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“…Fig. S3) 61 . Interestingly, MCF10A cells tended to show sustained p53 accumulation already at 39 °C.…”

Section: Resultsmentioning

confidence: 99%

“…The female human non-transformed breast epithelial cell line MCF10A expressing p53-mVenus and p21-mCherry has been described before 61 . In brief, the coding sequence for fluorescent proteins was inserted in the endogenous gene loci using Cas9-mediated genome engineering.…”

Section: Methodsmentioning

confidence: 99%

p53 dynamics in single cells are temperature-sensitive

Jentsch

Snyder

Sheng

et al. 2020

Sci Rep

Self Cite

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“…Emi1 reaches its threshold during the late G1 phase [34]. In the S->G1 transition, p53 activates p21 and inhibits CycA, CycE, and E2F, which suggests that the S->G1 transition might be caused by the cellular DNA damaged [69].…”

Section: Discussionmentioning

confidence: 99%

Quantifying the Landscape and Transition Paths for Proliferation–Quiescence Fate Decisions

Chen

2020

JCM

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The cell cycle, essential for biological functions, experiences delicate spatiotemporal regulation. The transition between G1 and S phase, which is called the proliferation–quiescence decision, is critical to the cell cycle. However, the stability and underlying stochastic dynamical mechanisms of the proliferation–quiescence decision have not been fully understood. To quantify the process of the proliferation–quiescence decision, we constructed its underlying landscape based on the relevant gene regulatory network. We identified three attractors on the landscape corresponding to the G0, G1, and S phases, individually, which are supported by single-cell data. By calculating the transition path, which quantifies the potential barrier, we built expression profiles in temporal order for key regulators in different transitions. We propose that the two saddle points on the landscape characterize restriction point (RP) and G1/S checkpoint, respectively, which provides quantitative and physical explanations for the mechanisms of Rb governing the RP while p21 controlling the G1/S checkpoint. We found that Emi1 inhibits the transition from G0 to G1, while Emi1 in a suitable range facilitates the transition from G1 to S. These results are partially consistent with previous studies, which also suggested new roles of Emi1 in the cell cycle. By global sensitivity analysis, we identified some critical regulatory factors influencing the proliferation–quiescence decision. Our work provides a global view of the stochasticity and dynamics in the proliferation–quiescence decision of the cell cycle.

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“…Among cell cycle regulatory proteins, p21 plays a direct role in inhibiting DNA replication [48]. In addition, E2F and PCNA integrate the cell cycle with DNA replication [49,50]. In eukaryotic cells, the MCM complex (known as DNA replication licensing) controls the once-per-cell cycle DNA replication process [51,52].…”

Section: Discussionmentioning

confidence: 99%

The Role of p53-Mediated Signaling in the Therapeutic Response of Colorectal Cancer to 9F, a Spermine-Modified Naphthalene Diimide Derivative

Gao

Wang

et al. 2020

Cancers

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Colorectal cancer (CRC) is one of the most prevalent cancers due to its frequency and high rate of mortality. Polyamine-vectorized anticancer drugs possess multiple biological properties. Of these drugs, 9F has been shown to inhibit tumor growth and the metastasis of hepatocellular carcinoma. This current study aims to investigate the effects of 9F on CRC and determine its molecular mechanisms of action. Our findings demonstrate that 9F inhibits CRC cell growth by inducing apoptosis and cell cycle arrest, and suppresses migration, invasion and angiogenesis in vitro, resulting in the inhibition of tumor growth and metastasis in vivo. Based on RNA-seq data, further bioinformatic analyses suggest that 9F exerts its anticancer activities through p53 signaling, which is responsible for the altered expression of key regulators of the cell cycle, apoptosis, the epithelial-to-mesenchymal transition (EMT), and angiogenesis. In addition, 9F is more effective than amonafide against CRC. These results show that 9F can be considered as a potential strategy for CRC treatment.

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PCNA-Mediated Degradation of p21 Coordinates the DNA Damage Response and Cell Cycle Regulation in Individual Cells

Cited by 34 publications

References 58 publications

p53 dynamics in single cells are temperature-sensitive

p53 dynamics in single cells are temperature-sensitive

Quantifying the Landscape and Transition Paths for Proliferation–Quiescence Fate Decisions

The Role of p53-Mediated Signaling in the Therapeutic Response of Colorectal Cancer to 9F, a Spermine-Modified Naphthalene Diimide Derivative

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