The p53 pathway is differentially activated in response to distinct DNA damage, leading to alternative phenotypic outcomes in mammalian cells. Recent evidence suggests that p53 expression dynamics ...play an important role in the differential regulation of cell fate, but questions remain as to how p53 dynamics and the subsequent cellular response are modulated by variable DNA damage.
We identified a novel, bimodal switch of p53 dynamics modulated by DNA-damage strength that is crucial for cell-fate control. After low DNA damage, p53 underwent periodic pulsing and cells entered cell-cycle arrest. After high DNA damage, p53 underwent a strong monotonic increase and cells activated apoptosis. We found that the damage dose-dependent bimodal switch was due to differential Mdm2 upregulation, which controlled the alternative cell fates mainly by modulating the induction level and pro-apoptotic activities of p53.
Our findings not only uncover a new mode of regulation for p53 dynamics and cell fate, but also suggest that p53 oscillation may function as a suppressor, maintaining a low level of p53 induction and pro-apoptotic activities so as to render cell-cycle arrest that allows damage repair.
Crucial transitions in cancer—including tumor initiation, local expansion, metastasis, and therapeutic resistance—involve complex interactions between cells within the dynamic tumor ecosystem. ...Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecedented resolution. The Human Tumor Atlas Network (HTAN), part of the National Cancer Institute (NCI) Cancer Moonshot Initiative, will establish a clinical, experimental, computational, and organizational framework to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. This effort complements both ongoing efforts to map healthy organs and previous large-scale cancer genomics approaches focused on bulk sequencing at a single point in time. Generating single-cell, multiparametric, longitudinal atlases and integrating them with clinical outcomes should help identify novel predictive biomarkers and features as well as therapeutically relevant cell types, cell states, and cellular interactions across transitions. The resulting tumor atlases should have a profound impact on our understanding of cancer biology and have the potential to improve cancer detection, prevention, and therapeutic discovery for better precision-medicine treatments of cancer patients and those at risk for cancer.
The Human Tumor Atlas Network outlines their ambitious plan to generate 3D, single-cell, multiparametric, and longitudinal maps of diverse tumor types.
Metastasis frequently develops from disseminated cancer cells that remain dormant after the apparently successful treatment of a primary tumour. These cells fluctuate between an immune-evasive ...quiescent state and a proliferative state liable to immune-mediated elimination
. Little is known about the clearing of reawakened metastatic cells and how this process could be therapeutically activated to eliminate residual disease in patients. Here we use models of indolent lung adenocarcinoma metastasis to identify cancer cell-intrinsic determinants of immune reactivity during exit from dormancy. Genetic screens of tumour-intrinsic immune regulators identified the stimulator of interferon genes (STING) pathway as a suppressor of metastatic outbreak. STING activity increases in metastatic progenitors that re-enter the cell cycle and is dampened by hypermethylation of the STING promoter and enhancer in breakthrough metastases or by chromatin repression in cells re-entering dormancy in response to TGFβ. STING expression in cancer cells derived from spontaneous metastases suppresses their outgrowth. Systemic treatment of mice with STING agonists eliminates dormant metastasis and prevents spontaneous outbreaks in a T cell- and natural killer cell-dependent manner-these effects require cancer cell STING function. Thus, STING provides a checkpoint against the progression of dormant metastasis and a therapeutically actionable strategy for the prevention of disease relapse.
The endogenous circadian clock synchronizes with environmental time by appropriately resetting its phase in response to external cues. Of note, some resetting stimuli induce attenuated oscillations ...of clock output, which has been observed at the population-level in several organisms and in studies of individual humans. To investigate what is happening in individual cellular clocks, we studied the unicellular cyanobacterium S. elongatus. By measuring its phase-resetting responses to temperature changes, we found that population-level arrhythmicity occurs when certain perturbations cause stochastic phases of oscillations in individual cells. Combining modeling with experiments, we related stochastic phasing to the dynamical structure of the cyanobacterial clock as an oscillator and explored the physiological relevance of the oscillator structure for accurately timed rhythmicity in changing environmental conditions. Our findings and approach can be applied to other biological oscillators.
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•Phase resetting by temperature reveals stochastic responses in single-cellular clocks•A stable limit cycle enclosing an unstable singularity captures the cyanobacterial clock•Temperature entrains the clock by regulating the geometric structure of limit cycle•Resetting stimuli bringing the clock to the unstable singularity cause stochastic phases
Gan and O’Shea found that environmental signals can elicit stochastic circadian clock phases in individual cyanobacterial cells and quantitatively explained this phenomenon in terms of the dynamical properties of the clock. These properties are physiologically relevant for accurately timed rhythmicity in changing environmental conditions.
The endogenous circadian clock synchronizes with environmental time by appropriately resetting its phase in response to external cues. Of note, some resetting stimuli induce attenuated oscillations ...of clock output, which has been observed at the population-level in several organisms and in studies of individual humans. To investigate what is happening in individual cellular clocks, we studied the unicellular cyanobacterium S. elongatus. By measuring its phase resetting responses to temperature changes, we found that population-level arrhythmicity occurs when certain perturbations cause stochastic phases of oscillations in individual cells. Combining modeling with experiments, we related stochastic phasing to the dynamical structure of the cyanobacterial clock as an oscillator, and explored the physiological relevance of the oscillator structure for accurately-timed rhythmicity in changing environmental conditions. Our findings and approach can be applied to other biological oscillators.
Poly(ADP-ribose)ylation or PARylation by PAR polymerase 1 (PARP1) and dePARylation by poly(ADP-ribose) glycohydrolase (PARG) are equally important for the dynamic regulation of DNA damage response. ...PARG, the most active dePARylation enzyme, is recruited to sites of DNA damage via pADPr-dependent and PCNA-dependent mechanisms. Targeting dePARylation is considered an alternative strategy to overcome PARP inhibitor resistance. However, precisely how dePARylation functions in normal unperturbed cells remains elusive. To address this challenge, we conducted multiple CRISPR screens and revealed that dePARylation of S phase pADPr by PARG is essential for cell viability. Loss of dePARylation activity initially induced S-phase-specific pADPr signaling, which resulted from unligated Okazaki fragments and eventually led to uncontrolled pADPr accumulation and PARP1/2-dependent cytotoxicity. Moreover, we demonstrated that proteins involved in Okazaki fragment ligation and/or base excision repair regulate pADPr signaling and cell death induced by PARG inhibition. In addition, we determined that PARG expression is critical for cellular sensitivity to PARG inhibition. Additionally, we revealed that PARG is essential for cell survival by suppressing pADPr. Collectively, our data not only identify an essential role for PARG in normal proliferating cells but also provide a potential biomarker for the further development of PARG inhibitors in cancer therapy.
Deubiquitylating enzymes (DUBs) remove ubiquitin chains from proteins and regulate protein stability and function. USP7 is one of the most extensively studied DUBs, since USP7 has several well-known ...substrates important for cancer progression, such as MDM2, N-MYC, and PTEN. Thus, USP7 is a promising drug target. However, systematic identification of USP7 substrates has not yet been performed. In this study, we carried out proteome profiling with label-free quantification in control and single/double-KO cells of
and its closest homolog,
Our proteome profiling for the first time revealed the proteome changes caused by
and/or
depletion. Combining protein profiling, transcriptome analysis, and tandem affinity purification of USP7-associated proteins, we compiled a list of 20 high-confidence USP7 substrates that includes known and novel USP7 substrates. We experimentally validated MGA and PHIP as new substrates of USP7. We further showed that MGA deletion reduced cell proliferation, similar to what was observed in cells with
deletion. In conclusion, our proteome-wide analysis uncovered potential USP7 substrates, providing a resource for further functional studies.
Increasing coastal pollution leads to frequent algal blooms, but little is known on the effect of growth and development in organisms with increasing algal concentration. In recent years, the clam ...Cyclina sinensis has been an important marine economic shellfish that is widely cultivated. This study investigated the effects of different Chlorella concentrations (5 × 105 cell/L (Diet T1), 1.25 × 106 cell/L (Diet T2), 1.3 × 107 cell/L (Diet T3), 1.25 × 108 cell/L (Diet T4), and 1.5 × 109 cell/L (Diet T5)) on the growth, enzyme activities of digestive, immune, and respiratory metabolism, and hepatopancreatic transcriptome gene expression characteristic response of C. sinensis. Results showed that the shell length growth rate, shell height growth rate, and survival rate of C. sinensis significantly decreased as the Chlorella concentration reached 5 × 105 cell/L. The condition factor of C. sinensis in Diet T1 and the hepatopancreas index of C. sinensis in Diet T4 were significantly higher than those in the other groups (P < 0.05). The enzyme activities of superoxide dismutase increased significantly with the rise in concentration of Chlorella, but the highest lysozyme in the hepatopancreas of C. sinensis was observed in the Diet T1 group. The enzyme activities of acid phosphatase and amylase in Diet T3, trypsin in Diet T5, lipase and succinate dehydrogenase in Diet T4, and lactate dehydrogenase in Diet T1 of C. sinensis were significantly higher than those in the other groups (P < 0.05). These results suggest that some enzyme activities related to digestion, metabolism, and respiration are inhibited with the Chlorella concentration increased. Furthermore, transcriptome results showed that the expression levels of G6P, IGFBP, CHI3L1, FAS, MyHC, and other genes related to glucose, protein, and fatty acid metabolism of C. sinensis were significantly downregulated in the Diet T3 and Diet T5 groups. All these results suggest that Chlorella concentrations above 5 × 105 cell/L should be avoided in practice. This study provides a scientific basis for C. sinensis culture and further extends the understanding of the metabolism of bivalves with diet concentration.
•Chlorella concentrations above 5×105 cell/L inhibited the growth of the C. sinensis.•Diet concentration effected the enzyme activities related to digestion, immune, and respiration metabolism.•This study investigated the hepatopancreatic gene transcriptional levels of C. sinensis on different diet concentrations.
A breakthrough "Green Revolution" in rice enhanced lodging resistance by using gibberellin-deficient semi-dwarf varieties. However, the gibberellic acid (GA) signaling regulation on rice disease ...resistance remains unclear. The resistance test showed that a positive GA signaling regulator
mutant
was more susceptible while a negative GA signaling regulator
(
) mutant was less susceptible to sheath blight (ShB), one of the major rice diseases, suggesting that GA signaling positively regulates ShB resistance. To isolate the regulator, which simultaneously regulates rice lodging and ShB resistance, SLR1 interactors were isolated. Yeast two-hybrid (Y2H), bimolecular fluorescence complementation (BiFC), and Co-IP assay results indicate that SLR1 interacts with Calcineurin B-like-interacting protein kinase 31 (CIPK31).
mutants exhibited normal plant height, but
showed semi-dwarfism. In addition, the SLR1 level was much higher in
than in the wild-type, suggesting that
might accumulate SLR1 to inhibit GA signaling and thus regulate its semi-dwarfism. Recently, we demonstrated that CIPK31 interacts and inhibits Catalase C (CatC) to accumulate ROS, which promotes rice disease resistance. Interestingly, CIPK31 interacts with Vascular Plant One Zinc Finger 2 (VOZ2) in the nucleus, and expression of CIPK31 accumulated VOZ2. Inoculation of
AG1-IA revealed that the
mutant was more susceptible to ShB. Thus, these data prove that CIPK31 promotes lodging and ShB resistance by regulating GA signaling and VOZ2 in rice. This study provides a valuable reference for rice ShB-resistant breeding.
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