scholarly journals Human Papillomaviruses Target the DNA Damage Repair and Innate Immune Response Pathways to Allow for Persistent Infection

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1390
Author(s):  
Elona Gusho ◽  
Laimonis Laimins
Keyword(s):  
Immune Response ◽  
Dna Damage ◽  
High Risk ◽  
Persistent Infection ◽  
Ataxia Telangiectasia ◽  
Dna Damage Repair ◽  
Immune Surveillance ◽  
Human Papillomaviruses ◽  
Innate Immune ◽  
Damage Repair

Persistent infection with high-risk human papillomaviruses (HPVs) is the major risk factor associated with development of anogenital and oropharyngeal cancers. Initial infection by HPVs occurs into basal epithelial cells where viral genomes are established as nuclear episomes and persist until cleared by the immune response. Productive replication or amplification occurs upon differentiation and is dependent upon activation of the ataxia-telangiectasia mutated (ATM), ataxia telangiectasia and RAD3-related (ATR) DNA damage repair (DDR) pathways. In addition to activating DDR pathways, HPVs must escape innate immune surveillance mechanisms by antagonizing sensors, adaptors, interferons and antiviral gene expression. Both DDR and innate immune pathways are key host mechanisms that crosstalk with each other to maintain homeostasis of cells persistently infected with HPVs. Interestingly, it is still not fully understood why some HPV infections get cleared while others do not. Targeting of these two processes with antiviral therapies may provide opportunities for treatment of cancers caused by high-risk HPVs.

scholarly journals STAT-5 Regulates Transcription of the Topoisomerase IIβ-Binding Protein 1 (TopBP1) Gene To Activate the ATR Pathway and Promote Human Papillomavirus Replication

mBio ◽  
2015 ◽  
Vol 6 (6) ◽  
Author(s):  
Shiyuan Hong ◽  
Shouqiang Cheng ◽  
Andre Iovane ◽  
Laimonis A. Laimins
Keyword(s):  
Dna Damage ◽  
Life Cycle ◽  
High Risk ◽  
Viral Replication ◽  
Ataxia Telangiectasia ◽  
Human Papillomaviruses ◽  
Innate Immune ◽  
Strand Breaks ◽  
Differentiated Cells ◽  
Copy Numbers

ABSTRACTThe life cycle of high-risk human papillomaviruses (HPVs) is dependent upon epithelial differentiation. Following infection of basal cells, HPV genomes are stably maintained at low copy numbers, and productive replication or amplification is restricted to highly differentiated suprabasal cells. In high-risk HPV infections, the ATM pathway is constitutively activated in the absence of external DNA-damaging agents and is required for productive viral replication. The ataxia telangiectasia (ATM) pathway repairs double-strand breaks in DNA, while the ataxia telangiectasia and Rad3-related (ATR) pathway targets single-strand breaks. Our studies show that the ATR pathway, like the ATM pathway, is activated in HPV-positive cells and that inhibitors of ATR or CHK1 phosphorylation block both amplification and late viral gene expression in differentiated cells while moderately reducing stable copy numbers in undifferentiated cells. TopBP1 is a critical upstream activator of the ATR pathway and is expressed at elevated levels in HPV-positive cells. This increased expression of TopBP1 is necessary for ATR/CHK1 activation in HPV-positive cells, and knockdown blocks amplification. Furthermore, TopBP1 activation is shown to be regulated at the level of transcription initiation by the innate immune regulator STAT-5, which is activated by HPV proteins. STAT-5 has also been shown to be a regulator of the ATM response, demonstrating that these two pathways are coordinately regulated in HPV-positive cells. These findings identify a novel link between the innate immune response and activation of the ATR DNA damage response in regulating the life cycle of high-risk HPVs.IMPORTANCEHigh-risk human papillomaviruses (HPVs) are the causative agents of cervical and other anogenital cancers, as well as many oral cancers. HPVs infect epithelial cells and restrict productive viral replication or amplification and virion production to differentiated cells. Our studies demonstrate that HPVs activate the ATR single-strand DNA repair pathway and this activation is necessary for HPV genome amplification. The innate immune regulator STAT-5 is shown to regulate transcription of the ATR binding factor TopBP1, and this is critical for the induction of the ATR pathway. Our study identifies important links between innate immune signaling, the ATR DNA damage pathway, and productive HPV replication that may lead to the characterization of new targets for the development of therapeutics to treat HPV-induced infections.

scholarly journals Genomic Instability and DNA Damage Repair Pathways Induced by Human Papillomaviruses

Viruses ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1821
Author(s):  
Takeyuki Kono ◽  
Laimonis Laimins
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Tumor Development ◽  
Human Papillomaviruses ◽  
Innate Immune ◽  
Genomic Integrity ◽  
Cytidine Deaminases ◽  
Damage Repair ◽  
Causative Agents ◽  
Apobec3 Family

Human papillomaviruses (HPV) are the causative agents of cervical and other anogenital cancers as well as those of the oropharynx. HPV proteins activate host DNA damage repair factors to promote their viral life cycle in stratified epithelia. Activation of both the ATR pathway and the ATM pathway are essential for viral replication and differentiation-dependent genome amplification. These pathways are also important for maintaining host genomic integrity and their dysregulation or mutation is often seen in human cancers. The APOBEC3 family of cytidine deaminases are innate immune factors that are increased in HPV positive cells leading to the accumulation of TpC mutations in cellular DNAs that contribute to malignant progression. The activation of DNA damage repair factors may corelate with expression of APOBEC3 in HPV positive cells. These pathways may actively drive tumor development implicating/suggesting DNA damage repair factors and APOBEC3 as possible therapeutic targets.

scholarly journals Diverse immune response of DNA damage repair-deficient tumors

2021 ◽  
Vol 2 (5) ◽  
pp. 100276
Author(s):  
Tao Qing ◽  
Tomi Jun ◽  
Katherine E. Lindblad ◽  
Amaia Lujambio ◽  
Michal Marczyk ◽  
...  
Keyword(s):  
Immune Response ◽  
Dna Damage ◽  
Dna Damage Repair ◽  
Damage Repair

scholarly journals Identification of Genetic Determinants of Pancreatic Cancer Immune Phenotypes by Integrative Genome-scale Analysis

2021 ◽  
Author(s):  
Yuhang Ling ◽  
Jiaqi Xu ◽  
Xuedong Wang ◽  
Jie Song ◽  
Qiuhui Qian ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Immune Response ◽  
Dna Damage ◽  
Immune System ◽  
Immune Cell ◽  
Dna Damage Repair ◽  
Cell Interactions ◽  
Tumor Microenvironments ◽  
Damage Repair ◽  
Immune Phenotypes

Abstract Background Pancreatic cancer (PC) is a malignant neoplasm of the digestive tract that is highly malignant and difficult to diagnose at an early stage with high postoperative mortality and low cure rates. Cancer immunotherapy is innovating the clinical treatment of several cancers, but has a limited role in PC. The incomplete understanding of immune response hinders the development of gene therapy. To fill this gap, it is very necessary to classify the immunogenic subtypes of PC to understand the relationship between tumor microenvironments and clinical pathological characteristics, DNA damage repair and tumor immune response.Methods We extracted copy number change, somatic mutation and expression data from tumor genome map (TCGA). Using RNA sequencing data, we defined three different immunophenotypes and elucidated how immune cell interactions in immune subtypes vary with the background of the immune system. Further correlation analysis between DNA damage repair (DDR) related genes expression and immune response was conducted to explore the effects of DDR expression on antitumor activity in the tumor microenvironments.Results We defined three different immunophenotypes and elucidated how immune cell interactions in immune subtypes vary with the background of the immune system. When the total number of mutations was standardized, no enrichment of new epitopes was detected in immunocompetent phenotypes. These observations suggest that mutations in Th-1 enriched IS3 tumors are essentially no more immunogenic than those in IS2 cancers. We also found that the expression patterns of key IFN mediators STAT1 and / or STAT3 were increased in tumors with DDR mutations (19 of ATM, ERCC1, Rb1, BRCA2, pole and TP53), which is a reflex activation of IFN pathway.Conclusions Three defined immune subtypes show different characteristics of immune cell infiltration, revealing different manifestations in anti-cancer immune function. That is to say, clinical biological events of differential tumors are associated to immune-phenotypes. The invasive phenotype was driven by somatic mutations across immune subtypes, and DDR defect may also influence the response of tumor immune subtypes. Our results suggested that the occurrence of pancreatic cancer is related to genetic factors of immunophenotype, providing information for clinical prognosis and outcome of pancreatic cancer.

scholarly journals A Prognostic DNA Damage Repair Genes Signature and Its Impact on Immune Cell Infiltration in Glioma

2021 ◽  
Vol 11 ◽  
Author(s):  
Guohui Wang ◽  
Huandi Zhou ◽  
Lei Tian ◽  
Tianfang Yan ◽  
Xuetao Han ◽  
...  
Keyword(s):  
Dna Damage ◽  
High Risk ◽  
Cox Regression ◽  
Dna Damage Repair ◽  
Risk Groups ◽  
Immune Microenvironment ◽  
Damage Repair ◽  
Immunosuppressive Cells ◽  
Repair Genes ◽  
Genome Atlas

ObjectiveGlioma is the most frequent type of malignant cerebral tumors. DNA damage repair genes (DDRGs) play a crucial role in the development of cancer. In this study, we constructed a DDRGs signature and investigated the potential mechanisms involved in this disease.MethodsRNA sequence data, microarray data, and corresponding clinical information of gliomas were downloaded from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO). Subsequently, we identified candidate genes by differential analysis and Cox regression analysis. The least absolute shrinkage and selection operator Cox regression model was utilized to construct a DDRGs signature using TCGA training dataset. According to this signature, patients with glioma were divided into low- and high-risk groups. The predictive ability of the signature was validated by prognostic analysis, receiver operating characteristic curves, principal component analysis, and stratification analysis in TCGA testing and CGGA verification datasets. CIBERSORT and single-sample gene set enrichment analysis (ssGSEA) were used to evaluate the immune microenvironment of glioma. Moreover, we conducted GSEA to determine the functions and pathways in the low- and high-risk groups. Finally, a nomogram was constructed by combining the signature and other clinical features.ResultsA total of 1,431 samples of glioma (592 from TCGA, 686 from the CGGA, and 153 from the GEO) and 23 samples of normal brain tissue from the GEO were analyzed in this study. There were 51 prognostic differentially expressed DDRGs. Additionally, five DDRGs (CDK4、HMGB2、WEE1、SMC3 and GADD45G) were selected to construct a DDRGs signature for glioma, stratifying patients into low- and high-risk groups. The survival analysis showed that the DDRGs signature could differentiate the outcome of the low- and high-risk groups, showing that high-risk gliomas were associated with shorter overall survival. The immune microenvironment analysis revealed that more immunosuppressive cells, such as tumor associated macrophages and regulatory T cells, were recruited in the high-risk group. GSEA also showed that high-risk glioma was correlated with the immune and extracellular matrix pathways.ConclusionThe five DDRGs signature and its impact on the infiltration of immunosuppressive cells could precisely predict the prognosis and provide guidance on the treatment of glioma.

scholarly journals Novel Insights into the Molecular Regulation of Ribonucleotide Reductase in Adrenocortical Carcinoma Treatment

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4200
Author(s):  
Christina Bothou ◽  
Ashish Sharma ◽  
Adrian Oo ◽  
Baek Kim ◽  
Pal Perge ◽  
...  
Keyword(s):  
Dna Damage ◽  
Ribonucleotide Reductase ◽  
Ataxia Telangiectasia ◽  
Therapeutic Option ◽  
Treatment Options ◽  
Dna Damage Repair ◽  
Repair System ◽  
Clinical Patient ◽  
Damage Repair ◽  
Adrenocortical Carcinomas

Current systemic treatment options for patients with adrenocortical carcinomas (ACCs) are far from being satisfactory. DNA damage/repair mechanisms, which involve, e.g., ataxia-telangiectasia-mutated (ATM) and ataxia-telangiectasia/Rad3-related (ATR) protein signaling or ribonucleotide reductase subunits M1/M2 (RRM1/RRM2)-encoded ribonucleotide reductase (RNR) activation, commonly contribute to drug resistance. Moreover, the regulation of RRM2b, the p53-induced alternative to RRM2, is of unclear importance for ACC. Upon extensive drug screening, including a large panel of chemotherapies and molecular targeted inhibitors, we provide strong evidence for the anti-tumoral efficacy of combined gemcitabine (G) and cisplatin (C) treatment against the adrenocortical cell lines NCI-H295R and MUC-1. However, accompanying induction of RRM1, RRM2, and RRM2b expression also indicated developing G resistance, a frequent side effect in clinical patient care. Interestingly, this effect was partially reversed upon addition of C. We confirmed our findings for RRM2 protein, RNR-dependent dATP levels, and modulations of related ATM/ATR signaling. Finally, we screened for complementing inhibitors of the DNA damage/repair system targeting RNR, Wee1, CHK1/2, ATR, and ATM. Notably, the combination of G, C, and the dual RRM1/RRM2 inhibitor COH29 resulted in previously unreached total cell killing. In summary, we provide evidence that RNR-modulating therapies might represent a new therapeutic option for ACC.

scholarly journals Pathogenesis of Human Papillomaviruses Requires the ATR/p62 Autophagy-Related Pathway

mBio ◽  
2020 ◽  
Vol 11 (4) ◽  
Author(s):  
Shiyuan Hong ◽  
Yan Li ◽  
Paul J. Kaminski ◽  
Jorge Andrade ◽  
Laimonis A. Laimins
Keyword(s):  
Dna Damage ◽  
Transcription Factor ◽  
High Risk ◽  
Viral Replication ◽  
Human Papillomaviruses ◽  
Negative Effects ◽  
Genome Amplification ◽  
Inflammatory Genes ◽  
Damage Repair ◽  
Cargo Protein

ABSTRACT High-risk human papillomaviruses (HPVs) constitutively activate the ataxia telangiectasia and Rad3-related (ATR) DNA damage response pathway, and this is required for viral replication. In fibroblasts, activated ATR regulates transcription of inflammatory genes through its negative effects on the autophagosome cargo protein p62. In addition, suppression of p62 results in increased levels of the transcription factor GATA4, leading to cellular senescence. In contrast, in HPV-positive keratinocytes, we observed that activation of ATR resulted in increased levels of phosphorylated p62, which in turn lead to reduced levels of GATA4. Knockdown of ATR in HPV-positive cells resulted in decreased p62 phosphorylation and increased GATA4 levels. Transcriptome sequencing (RNA-seq) analysis of HPV-positive cells identified inflammatory genes and interferon factors as negative transcriptional targets of ATR. Furthermore, knockdown of p62 or overexpression of GATA4 in HPV-positive cells leads to inhibition of viral replication. These findings identify a novel role of the ATR/p62 signaling pathway in HPV-positive cells. IMPORTANCE High-risk human papillomaviruses (HPVs) infect epithelial cells and induce viral genome amplification upon differentiation. HPV proteins activate the ATR DNA damage repair pathway, and this is required for HPV genome amplification. In the present study, we show that HPV-induced ATR activation also leads to suppression of expression of inflammatory response genes. This suppression results from HPV-induced phosphorylation of the autophagosome cargo protein p62 which regulates the levels of the transcription factor GATA4. Activation of p62 in normal fibroblasts results in senescence, but this is not seen in HPV-positive keratinocytes. Importantly, knockdown of p62 or overexpression of GATA4 in HPV-positive cells abrogates viral replication. This study demonstrates that activation of ATR in HPV-positive cells triggers a p62-directed pathway inducing suppression of inflammatory gene expression independent of DNA repair and facilitating HPV replication.

scholarly journals MicroRNA-18a Attenuates DNA Damage Repair through Suppressing the Expression of Ataxia Telangiectasia Mutated in Colorectal Cancer

PLoS ONE ◽  
2013 ◽  
Vol 8 (2) ◽  
pp. e57036 ◽  
Author(s):  
Chung-Wah Wu ◽  
Yu-Juan Dong ◽  
Qiao-Yi Liang ◽  
Xin-Qi He ◽  
Simon S. M. Ng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Ataxia Telangiectasia ◽  
Dna Damage Repair ◽  
Ataxia Telangiectasia Mutated ◽  
Damage Repair
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