Exonucleases: Degrading DNA to Deal with Genome Damage, Cell Death, Inflammation and Cancer

Manils, Joan; Marruecos, Laura; Soler, Concepció

doi:10.3390/cells11142157

Cited by 7 publications

(7 citation statements)

References 240 publications

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“…Exonucleases are also of interest as potential targets of anticancer drugs. More than ten exo- and endonucleases are active in different forms of mammalian DNA repair (reviewed in 38 ). Furthermore, upregulation of EXO1 is associated with increased malignancies and correlated with a poor prognosis 39,40 , whereas the inhibition of APE2 has shown to reduce growth and malignancies 41,42 .…”

Section: Resultsmentioning

confidence: 99%

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A high-throughput exonuclease assay based on the fluorescent base analog 2-aminopurine

Botto

Murthy

Lamers

2022

Preprint

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Exonucleases are essential enzymes that remove nucleotides from free DNA ends during DNA replication, DNA repair and telomere maintenance. Due to their essential role, they are potential targets for novel anticancer and antimicrobial drugs but have so far have been little exploited. Here we present a simple and versatile real-time exonuclease assay based on 2-aminopurine, an intrinsically fluorescent nucleotide that is quenched by neighboring bases when embedded in DNA. We show that our assay is applicable to different eukaryotic and bacterial exonucleases acting on both 3' and 5' DNA ends, over a wide range of protein activities and suitable for a high throughput inhibitor screening campaign. Using our assay, we discover a novel inhibitor of the Mycobacterium tuberculosis PHP-exonuclease that is part of the replicative DNA polymerase DnaE1. Hence, our novel assay will be a useful tool for high throughput screening for novel exonuclease inhibitors that may interfere with DNA replication or DNA maintenance.

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Section: Resultsmentioning

confidence: 99%

“…Exonucleases are also of interest as potential targets of anticancer drugs. More than ten exo-and endonucleases are active in different forms of mammalian DNA repair (reviewed in 38 ).…”

Section: Discussion and Concluding Remarksmentioning

confidence: 99%

A high-throughput exonuclease assay based on the fluorescent base analog 2-aminopurine

Botto

Murthy

Lamers

2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Exonucleases are also of interest as potential targets of anticancer drugs. More than 10 exo- and endonucleases are active in different forms of mammalian DNA repair (reviewed in ref ). Furthermore, upregulation of EXO1 is associated with increased malignancies and correlated with a poor prognosis, , whereas the inhibition of APE2 has shown to reduce growth and malignancies. , Finally, ExoN, the replicative exonuclease of the SARS-CoV-2 virus, is also the target of novel promising antiviral drugs …”

Section: Discussion and Concluding Remarksmentioning

confidence: 99%

High-Throughput Exonuclease Assay Based on the Fluorescent Base Analogue 2-Aminopurine

2023

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Exonucleases are essential enzymes that remove nucleotides from free DNA ends during DNA replication, DNA repair, and telomere maintenance. Due to their essential role, they are potential targets for novel anticancer and antimicrobial drugs but have so far been little exploited. Here, we present a simple and versatile real-time exonuclease assay based on 2-aminopurine, an intrinsically fluorescent nucleotide that is quenched by neighboring bases when embedded in DNA. We show that our assay is applicable to different eukaryotic and bacterial exonucleases acting on both 3′ and 5′ DNA ends over a wide range of protein activities and suitable for a high-throughput inhibitor screening campaign. Using our assay, we discover a novel inhibitor of the Mycobacterium tuberculosis PHP-exonuclease that is part of the replicative DNA polymerase DnaE1. Hence, our novel assay will be a useful tool for high-throughput screening for novel exonuclease inhibitors that may interfere with DNA replication or DNA maintenance.

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“…This gene panel could not only efficiently discriminate between these immune subtypes, but also serve as robust biomarkers for the identification of immune subtypes. The expression of these genes has been reported to be associated with different immune related functions in various cancers [38][39][40][41][42] and some are also used as biomarkers for predicting the efficacy of immunotherapy in various cancers [43][44][45]. Apart from imparting immune functions, the above-mentioned genes are also known to be involved in tumorigenesis of several cancers [39,44,[46][47][48][49][50][51][52][53][54][55], including CaCx [56][57][58].…”

Section: Discussionmentioning

confidence: 99%

Identification of HPV16 positive cervical cancer subsets characterized by divergent immune and oncogenic phenotypes with potential implications for immunotherapy

Ghosh

Sinha

et al. 2023

TUB

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BACKGROUND: Cervical cancers (CaCx), like many other cancer types, portray high molecular heterogeneity that affects response to therapy, including immunotherapy. In India and other developing countries, CaCx mortality rates are very high because women report to the clinics with advanced cancers in absence of organized screening programs. This calls for implementation of newer therapeutic regimens for CaCx, like immunotherapy, which is again not used commonly in such countries. OBJECTIVE: Therefore, we focused on dissecting tumour immune heterogeneity, if any, identify immune gene-based biomarkers of heterogeneity and subsets of such cancers with the potential for immunotherapy. We also attempted to characterize the cancer-associated phenotypes of such subsets, including viral load, to decipher the relationship of tumour immunogenicity with oncogenicity. METHODS: Employing RNA-seq analysis of 44 HPV16 positive CaCx patients, immune subtypes were identified by unsupervised hierarchical clustering of global immune-gene expression profiles. Proportions of tumor infiltrating immune cells in the tumor milieu were estimated, employing Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT), using gene expression data from RNA-seq. The oncogenic phenotypes of the immune subtypes of CaCx were deciphered through differential gene expression (DEGs) and pathway enrichment analysis. Viral load was estimated through TaqMan-based qRT-PCR analysis. RESULTS: Analysis revealed the presence of two immune subtypes of CaCx, A (26/44; 59.09%) and B (18/44; 40.90%). Compared to Subtype-A, Subtype-B portrayed overexpression of immune genes and high infiltration of immune cells, specifically CD8+ T cells (p < 0.0001). Besides, a significant correlation between PD-1 and PD-L1 co-expression among Subtype-B, as opposed to Subtype-A, confirmed the interactive roles of these immune checkpoint molecules in Subtype B. Stepwise discriminant analysis pin-pointed ten immune-genes that could classify 100% of the patients significantly (p < 0.0001) into the two immune subtypes and serve as potential biomarkers of CaCx immunity. Differential gene expression analysis between the subtypes unveiled that Subtype-B was more biologically aggressive than Subtype-A, reflecting loss of structural integrity and promotion of cancer progression. The viral load was significantly lower in Subtype-B (average viral load = 10.74/100 ng of genomic DNA) compared to Subtype-A (average viral load = 14.29/100 ng of genomic DNA). Thus viral load and the ten-gene panel underscore their association with immunogenicity and oncogenicity. CONCLUSION: Our study provides strong evidence that only a subset, about 41% of HPV16 positive CaCx patients in India, portray immune enrichment of the tumor milieu coupled with aggressive phenotypes. Such subtypes are therefore likely to benefit through checkpoint molecule-based or tumor infiltrating lymphocyte-based immunotherapy, which could be a leap forward in tackling aggressive forms of such CaCx in India and other developing countries.

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Exonucleases: Degrading DNA to Deal with Genome Damage, Cell Death, Inflammation and Cancer

Cited by 7 publications

References 240 publications

A high-throughput exonuclease assay based on the fluorescent base analog 2-aminopurine

A high-throughput exonuclease assay based on the fluorescent base analog 2-aminopurine

High-Throughput Exonuclease Assay Based on the Fluorescent Base Analogue 2-Aminopurine

Identification of HPV16 positive cervical cancer subsets characterized by divergent immune and oncogenic phenotypes with potential implications for immunotherapy

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