scholarly journals Aicardi-Goutières syndrome-associated gene SAMHD1 preserves genome integrity by preventing R-loop formation at transcription–replication conflict regions

PLoS Genetics ◽  
2021 ◽  
Vol 17 (4) ◽  
pp. e1009523
Author(s):  
Kiwon Park ◽  
Jeongmin Ryoo ◽  
Heena Jeong ◽  
Minsu Kim ◽  
Sungwon Lee ◽  
...  
Keyword(s):  
Survival Rate ◽  
Cancer Survival ◽  
Genome Instability ◽  
Cellular Responses ◽  
Genome Integrity ◽  
Loop Formation ◽  
Poor Survival ◽  
Anti Cancer ◽  
Samhd1 Expression ◽  
Underlying Mechanisms

The comorbid association of autoimmune diseases with cancers has been a major obstacle to successful anti-cancer treatment. Cancer survival rate decreases significantly in patients with preexisting autoimmunity. However, to date, the molecular and cellular profiles of such comorbidities are poorly understood. We used Aicardi-Goutières syndrome (AGS) as a model autoimmune disease and explored the underlying mechanisms of genome instability in AGS-associated-gene-deficient patient cells. We found that R-loops are highly enriched at transcription-replication conflict regions of the genome in fibroblast of patients bearing SAMHD1 mutation, which is the AGS-associated-gene mutation most frequently reported with tumor and malignancies. In SAMHD1-depleted cells, R-loops accumulated with the concomitant activation of DNA damage responses. Removal of R-loops in SAMHD1 deficiency reduced cellular responses to genome instability. Furthermore, downregulation of SAMHD1 expression is associated with various types of cancer and poor survival rate. Our findings suggest that SAMHD1 functions as a tumor suppressor by resolving R-loops, and thus, SAMHD1 and R-loop may be novel diagnostic markers and targets for patient stratification in anti-cancer therapy.

Novel Findings of Anti-cancer Property of Propofol

2018 ◽  
Vol 18 (2) ◽  
pp. 156-165 ◽  
Author(s):  
Jiaqiang Wang ◽  
Chien-shan Cheng ◽  
Yan Lu ◽  
Xiaowei Ding ◽  
Minmin Zhu ◽  
...  
Keyword(s):  
General Anesthesia ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Intravenous Anesthetic ◽  
The Past ◽  
Anti Cancer ◽  
Underlying Mechanisms ◽  
Recent Attention

Background: Propofol, a widely used intravenous anesthetic agent, is traditionally applied for sedation and general anesthesia. Explanation: Recent attention has been drawn to explore the effect and mechanisms of propofol against cancer progression in vitro and in vivo. Specifically, the proliferation-inhibiting and apoptosis-inducing properties of propofol in cancer have been studied. However, the underlying mechanisms remain unclear. Conclusion: This review focused on the findings within the past ten years and aimed to provide a general overview of propofol's malignance-modulating properties and the potential molecular mechanisms.

scholarly journals Vitamin E beyond Its Antioxidant Label

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 634
Author(s):  
Anca Ungurianu ◽  
Anca Zanfirescu ◽  
Georgiana Nițulescu ◽  
Denisa Margină
Keyword(s):  
Vitamin E ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Protective Effects ◽  
Cellular Effects ◽  
Inflammatory Status ◽  
Anti Cancer ◽  
Key Factor ◽  
Exciting Potential ◽  
Underlying Mechanisms

Vitamin E, comprising tocopherols and tocotrienols, is mainly known as an antioxidant. The aim of this review is to summarize the molecular mechanisms and signaling pathways linked to inflammation and malignancy modulated by its vitamers. Preclinical reports highlighted a myriad of cellular effects like modulating the synthesis of pro-inflammatory molecules and oxidative stress response, inhibiting the NF-κB pathway, regulating cell cycle, and apoptosis. Furthermore, animal-based models have shown that these molecules affect the activity of various enzymes and signaling pathways, such as MAPK, PI3K/Akt/mTOR, JAK/STAT, and NF-κB, acting as the underlying mechanisms of their reported anti-inflammatory, neuroprotective, and anti-cancer effects. In clinical settings, not all of these were proven, with reports varying considerably. Nonetheless, vitamin E was shown to improve redox and inflammatory status in healthy, diabetic, and metabolic syndrome subjects. The anti-cancer effects were inconsistent, with both pro- and anti-malignant being reported. Regarding its neuroprotective properties, several studies have shown protective effects suggesting vitamin E as a potential prevention and therapeutic (as adjuvant) tool. However, source and dosage greatly influence the observed effects, with bioavailability seemingly a key factor in obtaining the preferred outcome. We conclude that this group of molecules presents exciting potential for the prevention and treatment of diseases with an inflammatory, redox, or malignant component.

scholarly journals The splicing factor XAB2 interacts with ERCC1-XPF and XPG for R-loop processing

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Evi Goulielmaki ◽  
Maria Tsekrekou ◽  
Nikos Batsiotos ◽  
Mariana Ascensão-Ferreira ◽  
Eleftheria Ledaki ◽  
...  
Keyword(s):  
Dna Damage ◽  
Rna Splicing ◽  
Excision Repair ◽  
Intron Retention ◽  
Dna Lesions ◽  
Splicing Factor ◽  
Loop Formation ◽  
Rna Targets ◽  
Underlying Mechanisms

AbstractRNA splicing, transcription and the DNA damage response are intriguingly linked in mammals but the underlying mechanisms remain poorly understood. Using an in vivo biotinylation tagging approach in mice, we show that the splicing factor XAB2 interacts with the core spliceosome and that it binds to spliceosomal U4 and U6 snRNAs and pre-mRNAs in developing livers. XAB2 depletion leads to aberrant intron retention, R-loop formation and DNA damage in cells. Studies in illudin S-treated cells and Csbm/m developing livers reveal that transcription-blocking DNA lesions trigger the release of XAB2 from all RNA targets tested. Immunoprecipitation studies reveal that XAB2 interacts with ERCC1-XPF and XPG endonucleases outside nucleotide excision repair and that the trimeric protein complex binds RNA:DNA hybrids under conditions that favor the formation of R-loops. Thus, XAB2 functionally links the spliceosomal response to DNA damage with R-loop processing with important ramifications for transcription-coupled DNA repair disorders.

scholarly journals Finding an easy way to harmonize: a review of advances in clinical research and combination strategies of EZH2 inhibitors

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Chen Li ◽  
Yan Wang ◽  
Yueqing Gong ◽  
Tengrui Zhang ◽  
Jiaqi Huang ◽  
...  
Keyword(s):  
Treatment Modalities ◽  
Preclinical Studies ◽  
Combination Therapies ◽  
Tumor Treatment ◽  
Antitumor Effects ◽  
Therapeutic Modalities ◽  
Combination Strategies ◽  
Anti Cancer ◽  
Underlying Mechanisms ◽  
The Individual

AbstractEnhancer of zeste homolog 2 inhibitors (EZH2i) have garnered increased attention owing to their anticancer activity by targeting EZH2, a well-known cancer-promoting factor. However, some lymphomas are resistant to EZH2i, and EZH2i treatment alone is ineffective in case of EZH2-overexpressing solid tumors. The anti-cancer efficacy of EZH2i may be improved through safe and effective combinations of these drugs with other treatment modalities. Preclinical evidence indicates that combining EZH2i with other therapies, such as immunotherapy, chemotherapy, targeted therapy, and endocrine therapy, has complementary or synergistic antitumor effects. Therefore, elucidating the underlying mechanisms of the individual constituents of the combination therapies is fundamental for their clinical application. In this review, we have summarized notable clinical trials and preclinical studies using EZH2i, their progress, and combinations of EZH2i with different therapeutic modalities, aiming to provide new insights for tumor treatment.

Total ankle replacement: is pre-operative varus deformity a predictor of poor survival rate and clinical and radiological outcomes?

2018 ◽  
Vol 43 (1) ◽  
pp. 243-249 ◽  
Author(s):  
Federico Giuseppe Usuelli ◽  
Claudia Angela Di Silvestri ◽  
Riccardo D’Ambrosi ◽  
Annalisa Orenti ◽  
Filippo Randelli
Keyword(s):  
Survival Rate ◽  
Varus Deformity ◽  
Total Ankle Replacement ◽  
Poor Survival ◽  
Ankle Replacement

scholarly journals Sulforaphane suppresses autophagy during the malignant progression of gastric carcinoma via activating miR-4521/PIK3R3 pathway

2021 ◽  
pp. 096032712110544
Author(s):  
Zi-tan Peng ◽  
Pei Gu
Keyword(s):  
Cell Proliferation ◽  
Gastric Carcinoma ◽  
Carcinoma Cells ◽  
Malignant Progression ◽  
Gastric Carcinoma Cell ◽  
Over Expression ◽  
Anti Cancer ◽  
Underlying Mechanisms ◽  
Cruciferous Plants

Objective Sulforaphane, which exerts an effective anti-cancer ability, is a phytochemical converted from cruciferous plants. Here, we aimed to identify whether sulforaphane could suppress autophagy during the malignant progression of gastric carcinoma and to explore the underlying mechanisms. Methods SGC7901 cells were transfected with miR-4521 mimics, inhibitor, and pcDNA3.1- PIK3R3, and treated with sulforaphane or autophagy inhibitor. Cell proliferation, apoptosis, and miR-4521 or PIK3R3 expression were detected. Results MiR-4521 over-expression suppressed LC3-II/I ratio and Beclin-1 expression but induced p62 expression in SGC7901 cells. MiR-4521 also reduced gastric carcinoma cell proliferation and promoted apoptosis in vitro. In the mechanical observation, we identified that miR-4521 directly targeted PIK3R3 to repress its expression, and PIK3R3 up-regulation partly antagonized miR-4521-mediated autophagy, proliferation, and apoptosis in gastric carcinoma cells. In addition, sulforaphane exerted effective anti-cancer functions by repressing autophagy and growth in tumor cells at a concentration-dependent way. MiR-4521 inhibition or PIK3R3 over-expression weakened the anti-cancer functions of sulforaphane in gastric carcinoma cells. Conclusion Consequently, miR-4521 suppressed autophagy during the malignant progression of gastric carcinoma by targeting PIK3R3. Thus, miR-4521 may be applied as a therapeutic target for sulforaphane in gastric carcinoma.

scholarly journals The THP1-SAC3-SUS1-CDC31 Complex Works in Transcription Elongation-mRNA Export Preventing RNA-mediated Genome Instability

2008 ◽  
Vol 19 (10) ◽  
pp. 4310-4318 ◽  
Author(s):  
Cristina González-Aguilera ◽  
Cristina Tous ◽  
Belén Gómez-González ◽  
Pablo Huertas ◽  
Rosa Luna ◽  
...  
Keyword(s):  
Genome Instability ◽  
Cytidine Deaminase ◽  
Transcription Elongation ◽  
Mrna Export ◽  
Feedback Mechanism ◽  
Rnase H ◽  
Genome Integrity ◽  
Activation Induced Cytidine Deaminase ◽  
Specific Pathway ◽  
Mrnp Biogenesis

The eukaryotic THO/TREX complex, involved in mRNP biogenesis, plays a key role in the maintenance of genome integrity in yeast. mRNA export factors such as Thp1-Sac3 also affect genome integrity, but their mutations have other phenotypes different from those of THO/TREX. Sus1 is a novel component of SAGA transcription factor that also associates with Thp1-Sac3, but little is known about its effect on genome instability and transcription. Here we show that Thp1, Sac3, and Sus1 form a functional unit with a role in mRNP biogenesis and maintenance of genome integrity that is independent of SAGA. Importantly, the effects of ribozyme-containing transcription units, RNase H, and the action of human activation-induced cytidine deaminase on transcription and genome instability are consistent with the possibility that R-loops are formed in Thp1-Sac3-Sus1-Cdc31 as in THO mutants. Our data reveal that Thp1-Sac3-Sus1-Cdc31, together with THO/TREX, define a specific pathway connecting transcription elongation with export via an RNA-dependent dynamic process that provides a feedback mechanism for the control of transcription and the preservation of genetic integrity of transcribed DNA regions.

scholarly journals Single-Strand Break End Resection in Genome Integrity: Mechanism and Regulation by APE2

2018 ◽  
Vol 19 (8) ◽  
pp. 2389 ◽  
Author(s):  
Md. Hossain ◽  
Yunfeng Lin ◽  
Shan Yan
Keyword(s):  
Dna Damage ◽  
Genome Instability ◽  
Strand Break ◽  
Single Strand ◽  
Genome Integrity ◽  
Single Strand Break ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Damage Response ◽  
End Resection

DNA single-strand breaks (SSBs) occur more than 10,000 times per mammalian cell each day, representing the most common type of DNA damage. Unrepaired SSBs compromise DNA replication and transcription programs, leading to genome instability. Unrepaired SSBs are associated with diseases such as cancer and neurodegenerative disorders. Although canonical SSB repair pathway is activated to repair most SSBs, it remains unclear whether and how unrepaired SSBs are sensed and signaled. In this review, we propose a new concept of SSB end resection for genome integrity. We propose a four-step mechanism of SSB end resection: SSB end sensing and processing, as well as initiation, continuation, and termination of SSB end resection. We also compare different mechanisms of SSB end resection and DSB end resection in DNA repair and DNA damage response (DDR) pathways. We further discuss how SSB end resection contributes to SSB signaling and repair. We focus on the mechanism and regulation by APE2 in SSB end resection in genome integrity. Finally, we identify areas of future study that may help us gain further mechanistic insight into the process of SSB end resection. Overall, this review provides the first comprehensive perspective on SSB end resection in genome integrity.

Geographic Disparities in Cancer Survival and Access to Care

2012 ◽  
pp. 90-99
Author(s):  
Mary E. Gordinier ◽  
Carol L. Hanchette
Keyword(s):  
Ovarian Cancer ◽  
Survival Rate ◽  
Access To Care ◽  
Cancer Survival ◽  
The State ◽  
Registry Data ◽  
Cancer Registry Data ◽  
Ovarian Cancer Survival ◽  
Western Portion ◽  
Zip Code

From 1995-2005, ovarian cancer accounted for 2.7% of new cancer cases diagnosed among women in Kentucky and was responsible for 4.7% of female cancer deaths in the state. The five-year survival rate for ovarian cancer is 45% for all stages combined. Multiple studies document a survival advantage for women with gynecologic malignancies when treated by a gynecologic oncologist. The authors used Kentucky Cancer Registry data for the years 1995-2005, geocoded to 5-digit ZIP code, to examine the hypothesis that ovarian cancer survival is higher among patients receiving treatment in areas where gynecologic oncologists practice. Their hypothesis was confirmed. A secondary goal of the study was to identify geographic areas of the state with lower overall access to care. Contrary to the expected pattern of low access to care in the Appalachian region of the state, their analysis indicated that access to successful treatment is a greater issue in the western portion of Kentucky.

Cancer Survival Is (Mostly) Improving

Pained ◽  
2020 ◽  
pp. 245-246
Author(s):  
Michael D. Stein ◽  
Sandro Galea
Keyword(s):  
Prostate Cancer ◽  
United States ◽  
Pancreatic Cancer ◽  
Survival Rate ◽  
Cancer Diagnosis ◽  
Cancer Survival ◽  
Prostate Cancer Screening ◽  
Survival Rates ◽  
The United States ◽  
Cervical Cancers

This chapter discusses how the 5-year survival rates for the most common cancers in the United States improved by nearly 20% since the 1970s. While promising overall, low survival rates persist for pancreatic, liver, lung, esophageal, brain, and many other cancers. Meanwhile, 5-year survival for uterine and cervical cancers worsened. Pancreatic cancer has the lowest 5-year survival rate at 8.2%. In contrast, prostate cancer had the greatest 5-year survival increase from 67.8% to 98.6%, most likely reflecting a substantial uptick in prostate cancer screening and early detection. Five-year survival with leukemia also improved significantly, from 34.2% to 60.6%, likely resulting from improved treatments. As such, in both detection and treatment, the United States is making progress. For the millions of Americans who face a cancer diagnosis, this is cause for hope.

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