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2021 ◽  
Author(s):  
Daniel R Semlow ◽  
Victoria A MacKrell ◽  
Johannes Walter

The HMCES protein forms a covalent DNA-protein cross-link (DPC) with abasic (AP) sites in ssDNA, and the resulting HMCES-DPC is thought to suppress double-strand break formation in S phase. However, the dynamics of HMCES cross-linking and whether any DNA repair pathways normally include an HMCES-DPC intermediate remain unknown. Here, we show that an HMCES-DPC forms efficiently on the AP site generated during replication-coupled DNA interstrand cross-link (ICL) repair. We use this system to show that HMCES cross-links form on DNA after the replicative CMG helicase has passed over the AP site, and that HMCES is subsequently removed by the SPRTN protease. The HMCES-DPC suppresses DSB formation, slows translesion synthesis (TLS) past the AP site, and introduces a bias for insertion of deoxyguanosine opposite the AP site. These data show that HMCES-DPCs can form as constitutive intermediates in replication-coupled repair, and they suggest a general model of how HMCES protects AP sites during DNA replication.


2021 ◽  
Vol 118 (31) ◽  
pp. e2100178118
Author(s):  
Claire Armstrong ◽  
Sabrina L. Spencer

The current model of replication-dependent (RD) histone biosynthesis posits that RD histone gene expression is coupled to DNA replication, occurring only in S phase of the cell cycle once DNA synthesis has begun. However, several key factors in the RD histone biosynthesis pathway are up-regulated by E2F or phosphorylated by CDK2, suggesting these processes may instead begin much earlier, at the point of cell-cycle commitment. In this study, we use both fixed- and live-cell imaging of human cells to address this question, revealing a hybrid model in which RD histone biosynthesis is first initiated in G1, followed by a strong increase in histone production in S phase of the cell cycle. This suggests a mechanism by which cells that have committed to the cell cycle build up an initial small pool of RD histones to be available for the start of DNA replication, before producing most of the necessary histones required in S phase. Thus, a clear distinction exists at completion of mitosis between cells that are born with the intention of proceeding through the cell cycle and replicating their DNA and cells that have chosen to exit the cell cycle and have no immediate need for histone synthesis.


eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Liz Hernandez Borrero ◽  
David T Dicker ◽  
John Santiago ◽  
Jennifer Sanders ◽  
Xiaobing Tian ◽  
...  

Mutations in TP53 occur commonly in the majority of human tumors and confer aggressive tumor phenotypes, including metastasis and therapy resistance. CB002 and structural-analogs restore p53 signaling in tumors with mutant-p53 but we find that unlike other xanthines such as caffeine, pentoxifylline, and theophylline, they do not deregulate the G2 checkpoint. Novel CB002-analogs induce pro-apoptotic Noxa protein in an ATF3/4-dependent manner, whereas caffeine, pentoxifylline, and theophylline do not. By contrast to caffeine, CB002-analogs target an S-phase checkpoint associated with increased p-RPA/RPA2, p-ATR, decreased Cyclin A, p-histone H3 expression, and downregulation of essential proteins in DNA-synthesis and DNA-repair. CB002-analog #4 enhances cell death, and decreases Ki-67 in patient-derived tumor-organoids without toxicity to normal human cells. Preliminary in vivo studies demonstrate anti-tumor efficacy in mice. Thus, a novel class of anti-cancer drugs shows the activation of p53 pathway signaling in tumors with mutated p53, and targets an S-phase checkpoint.


2021 ◽  
Author(s):  
Yunshan Guo ◽  
Dingjun Hao

Abstract Background: The purpose of this study was to determine the role of Orai1 in the regulation of the proliferation and cell cycle of osteoblasts. Methods: The expression of Orai1 was inhibited by Orai1 small interfering RNA (siRNA) in MC3T3-E1 cells. Following Orai1 downregulation, cell proliferation and cell cycle were examined. Furthermore, the expression of cyclin D1, cyclin E, CDK4, and CDK6 was analyzed. The activity of the Ras-NF-κB signaling pathway was investigated to identify the role of Orai1 in the regulation of osteoblast proliferation. Results: Orai1 was successfully downregulated in MC3T3-E1 cells by the Orai1 siRNA transfection (p <0.05). We found that MC3T3-E1 cell proliferation was decreased, and the cell cycle was arrested by Orai1 downregulation (p <0.05). Additionally, the expression of cyclin D1 was decreased by Orai1 downregulation (p <0.05), as was the activity of the Ras-NF-κB signaling pathway (p <0.05). Orai1 siRNA did not further reduce cell proliferation, the proportion of cells in the S phase, and cyclin D1 expression after chemical blockage of the Ras signaling pathway in MC3T3-E1 cells (p >0.05).Conclusions: The results reveal that Orai1 downregulation may reduce cyclin D1 expression by inactivating the Ras-NF-κB signaling pathway thus blocking osteoblast proliferation and cell cycle.


Author(s):  
Mark Netanel ◽  
Andreas Samuel Eisermann ◽  
Alon Ziv

ABSTRACT Regional source-based earthquake early warning systems perform three consecutive tasks: (1) detection and epicenter location, (2) magnitude determination, and (3) ground-motion prediction. The correctness of the magnitude determination is contingent on that of the epicenter location, and the credibility of the ground-motion prediction depends on those of the epicenter location and the magnitude determination. Thus, robust epicenter location scheme is key for regional earthquake early warning systems. Available source-based systems yield acceptably accurate locations when the earthquakes occur inside the real-time seismic network, but they return erroneous results otherwise. In this study, a real-time algorithm that is intended as a supplement to an existing regional earthquake early warning systems is introduced with the sole objective of ameliorating its off-network location capacity. The new algorithm combines measurements from three or more network stations that are analyzed jointly using an array methodology to give the P-wave slowness vector and S-phase arrival time. Prior to the S-phase picking, the nonarrival of the S phase is used for determining a minimum epicentral distance. This estimate is updated repeatedly with elapsed time until the S phase is picked. Thus, the system timeliness is not compromised by waiting for the S-phase arrival. After the S wave is picked, an epicentral location can be determined using a single array by intersecting the back-azimuth beam with the S-minus-P annulus. When several arrays are assembled, the back azimuth and P and S picks from all arrays are combined to constrain the epicenter. The performance of the array processing for back azimuth and S-wave picking is assessed using a large number of accelerograms, recorded by nine strong motion sensors of the KiK-net seismic network in Japan. The nine stations are treated as three distinct seismic arrays, comprising three stations each. Good agreement is found between array-based and catalog-reported parameters. Finally, the advantage of the new array methodology with respect to alternative schemes for back azimuth and distance is demonstrated.


2021 ◽  
Author(s):  
Juanita C Limas ◽  
Aimee N. Littlejohn ◽  
Amy M. House ◽  
Katarzyna M Kedziora ◽  
Dalia Fleifel ◽  
...  

Cyclin E/CDK2 drives cell cycle progression from G1 to S phase. Cyclin E overproduction is toxic to mammalian cells, although the gene encoding cyclin E (CCNE1) is overexpressed in some cancers. It is not yet understood how cancer cells tolerate high levels of cyclin E. To address this question, we extensively characterized non-transformed epithelial cells subjected to chronic cyclin E overproduction. Cells overproducing human cyclin E briefly experienced truncated G1 phases, then consistently endured a transient period of DNA replication origin underlicensing, replication stress, and severely impaired proliferation. Individual cells displayed substantial intercellular heterogeneity in both cell cycle dynamics and CDK activity. Each of these phenotypes improved rapidly despite maintaining high cyclin E-associated activity. Transcriptome analysis revealed that adapted cells downregulated a cohort of G1-regulated genes. These cells also shared at least one unique change also found in breast tumors that overproduce cyclin E, expression of the cancer/testis antigen HORMAD1. Withdrawing cyclin E induction partially reversed the intermediate licensing phenotype of adapted cells indicating that adaptation is at least partly independent of genetic alterations. This study provides evidence that mammalian cyclin E/CDK inhibits origin licensing by an indirect mechanism through premature S phase onset. It serves as an example of specific oncogene adaptation that can identify key molecular changes during tumorigenesis.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Marta San Martin-Alonso ◽  
María E. Soler-Oliva ◽  
María García-Rubio ◽  
Tatiana García-Muse ◽  
Andrés Aguilera

AbstractIdentifying how R-loops are generated is crucial to know how transcription compromises genome integrity. We show by genome-wide analysis of conditional yeast mutants that the THO transcription complex, prevents R-loop formation in G1 and S-phase, whereas the Sen1 DNA-RNA helicase prevents them only in S-phase. Interestingly, damage accumulates asymmetrically downstream of the replication fork in sen1 cells but symmetrically in the hpr1 THO mutant. Our results indicate that: R-loops form co-transcriptionally independently of DNA replication; that THO is a general and cell-cycle independent safeguard against R-loops, and that Sen1, in contrast to previously believed, is an S-phase-specific R-loop resolvase. These conclusions have important implications for the mechanism of R-loop formation and the role of other factors reported to affect on R-loop homeostasis.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jessel Ayra-Plasencia ◽  
Cristina Ramos-Pérez ◽  
Silvia Santana-Sosa ◽  
Oliver Quevedo ◽  
Sara Medina-Suárez ◽  
...  

AbstractThe key role of Topoisomerase II (Top2) is the removal of topological intertwines between sister chromatids. In yeast, inactivation of Top2 brings about distinct cell cycle responses. In the case of the conditional top2-5 allele, interphase and mitosis progress on schedule but cells suffer from a chromosome segregation catastrophe. We here show that top2-5 chromosomes fail to enter a Pulsed-Field Gel Electrophoresis (PFGE) in the first cell cycle, a behavior traditionally linked to the presence of replication and recombination intermediates. We distinguished two classes of affected chromosomes: the rDNA-bearing chromosome XII, which fails to enter a PFGE at the beginning of S-phase, and all the other chromosomes, which fail at a postreplicative stage. In synchronously cycling cells, this late PFGE retention is observed in anaphase; however, we demonstrate that this behavior is independent of cytokinesis, stabilization of anaphase bridges, spindle pulling forces and, probably, anaphase onset. Strikingly, once the PFGE retention has occurred it becomes refractory to Top2 re-activation. DNA combing, two-dimensional electrophoresis, genetic analyses, and GFP-tagged DNA damage markers suggest that neither recombination intermediates nor unfinished replication account for the postreplicative PFGE shift, which is further supported by the fact that the shift does not trigger the G2/M checkpoint. We propose that the absence of Top2 activity leads to a general chromosome structural/topological change in mitosis.


Author(s):  
Keith A. Nolte ◽  
George P. Tsoflias

Abstract Seismicity in southern Kansas and northern Oklahoma in the past decade has been associated with fluid injections. In southcentral Kansas, the Wellington earthquake catalog is primarily composed of local, low-magnitude events. Approximately 22% of recorded earthquakes over a 2.5 yr period exhibit a seismic phase arriving between the direct P phase and direct S phase with particle motion similar to the P wave. This intermediate phase was identified as an S to P conversion (SP phase) occurring in the sedimentary rocks instead of the hypothesized basement to sedimentary section transition. We exploit the SP-converted phases to improve the depth accuracy of shallow earthquakes and to constrain VP/VS. The revised depth calculations further confirm that these local induced earthquakes are occurring in the shallow crystalline basement, below the sedimentary section in which fluids are injected.


2021 ◽  
Vol 12 ◽  
Author(s):  
Wenjie Zhu ◽  
Jian Xu ◽  
Zehao Chen ◽  
Jianxin Jiang

Hepatocellular carcinoma (HCC) is one of the most common carcinomas worldwide. Our study aims to analyze how NUSAP1 affects progression of HCC from clinical, molecular mechanism and immune perspectives. Firstly, we downloaded GSE62232, GSE102079, GSE112790, and GSE121248 gene expression profile datasets from GEO database. R studio was used to screen DEGs of each dataset, and 86 overlapping DEGs of the four datasets were screened at last. Then, CytoHubba plug-in in Cytoscape software was used to screen out NUSAP1 from the 86 DEGs. Subsequently, survival analysis, clinical correlation analysis, independent prognostic analysis, and GSEA enrichment analysis of NUSAP1 were analyzed using HCC patients from GSE76427 dataset, ICGC database, and TCGA database. The results revealed that HCC patients with higher expression level of NUSAP1 had a worse prognosis. NUSAP1 was an independent prognostic factor of HCC, and it may promote HCC progress by regulating cell cycle. To further elucidate its underlying molecular mechanism, we used cBioProtal online data analysis tool to screen all co-expression genes of NUSAP1 and used top 300 co-expression genes to accomplish KEGG and GO enrichment analysis; the results confirmed that NUSAP1 accelerated progression of HCC by regulating cell cycle. We continued to draw KEGG pathway map of cell cycle using co-expression genes enriched in cell cycle pathway by KEGG online tool. The map depicted that most of co-expression genes of NUSAP1 were located in S phase and G2/M phase of the cell cycle, and they could regulate the genes in G1 phase. To further understand the mechanism of cell cycle, we also did qRT-PCR, Western blot, and flow cytometry; the results showed that NUSAP1 was closely associated with CDK4, CDK6, and cyclinD1, which could regulate G1 to S phase transition. Besides, we also analyzed correlation between NUSAP1 and immune cells using HCC patients from GSE76427 dataset, ICGC database, and TCGA database. NUSAP1 was associated with some immune cells, and we speculated that NUSAP1 could also promote HCC progression by influencing T cell CD4 memory resting and macrophage M0 through some underlying mechanism.


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