Sml1 Inhibits the DNA Repair Activity of Rev1 in Saccharomyces cerevisiae during Oxidative Stress

Yao, Rui; Zhou, Pei; Wu, Chengjin; Li, Liming; Wu, Jing

doi:10.1128/aem.02838-19

Cited by 6 publications

(10 citation statements)

References 51 publications

(50 reference statements)

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“…DNA damage can also result in mutations and genomic instability without efficient repair, which underlies the malignant transformation of cells. Interestingly, emerging evidence has revealed that ROS/RNS can disrupt DNA repair pathways, including base excision repair (BER), direct reversal, and double-strand break repair [142,[172][173][174]. Patients with cancer exhibit lower BER efficiency than healthy participants, partially due to the ROS-dependent inhibition of DNA repair enzymes.…”

Section: Ros Drives Inflammation-induced Genomic Instabilitymentioning

confidence: 99%

Reactive Oxygen Species Bridge the Gap between Chronic Inflammation and Tumor Development

Long

et al. 2022

Oxidative Medicine and Cellular Longevity

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According to numerous animal studies, adverse environmental stimuli, including physical, chemical, and biological factors, can cause low-grade chronic inflammation and subsequent tumor development. Human epidemiological evidence has confirmed the close relationship between chronic inflammation and tumorigenesis. However, the mechanisms driving the development of persistent inflammation toward tumorigenesis remain unclear. In this study, we assess the potential role of reactive oxygen species (ROS) and associated mechanisms in modulating inflammation-induced tumorigenesis. Recent reports have emphasized the cross-talk between oxidative stress and inflammation in many pathological processes. Exposure to carcinogenic environmental hazards may lead to oxidative damage, which further stimulates the infiltration of various types of inflammatory cells. In turn, increased cytokine and chemokine release from inflammatory cells promotes ROS production in chronic lesions, even in the absence of hazardous stimuli. Moreover, ROS not only cause DNA damage but also participate in cell proliferation, differentiation, and apoptosis by modulating several transcription factors and signaling pathways. We summarize how changes in the redox state can trigger the development of chronic inflammatory lesions into tumors. Generally, cancer cells require an appropriate inflammatory microenvironment to support their growth, spread, and metastasis, and ROS may provide the necessary catalyst for inflammation-driven cancer. In conclusion, ROS bridge the gap between chronic inflammation and tumor development; therefore, targeting ROS and inflammation represents a new avenue for the prevention and treatment of cancer.

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Section: Ros Drives Inflammation-induced Genomic Instabilitymentioning

confidence: 99%

Reactive Oxygen Species Bridge the Gap between Chronic Inflammation and Tumor Development

Long

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…We confirm and quantify C. albicans DNA damage in the presence of antifungal drugs, and further find that numerous predicted error-prone polymerases (and related factors) are upregulated in the presence of DNA-damaging agents, including antifungal drugs. We further focus on REV1, which when deleted, leads to an increased mutation rate (in opposition to what is observed in S. cerevisiae [43][44][45] ), and a corresponding increase in evolved resistance to the antifungal drug caspofungin. Deletion of REV1 also causes a higher abundance of the protein Shm1, which is also involved in the C. albicans mutation rate.…”

Section: Introductionmentioning

confidence: 99%

A role for the putative error-prone polymeraseREV1in DNA damage and antifungal drug resistance inCandida albicans

Agyare-Tabbi,

Uthayakumar,

Francis

et al. 2024

Preprint

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Antimicrobial-induced DNA damage, and subsequent repair via upregulation of DNA repair factors, including error-prone translesion polymerases, can lead to the increased accumulation of mutations in the microbial genome, and ultimately increased risk of acquired mutations associated with antimicrobial resistance. While this phenotype is well described in bacterial species, it is less thoroughly investigated amongst microbial fungi. Here, we monitor DNA damage induced by antifungal agents in the fungal pathogenCandida albicans, and find that commonly used antifungal drugs are able to induce DNA damage, leading to the upregulation of transcripts encoding predicted error-prone polymerases and related factors. We focus onREV1, encoding a putative error-prone polymerase, and find that while deleting this gene inC. albicansleads to increased sensitivity to DNA damage, it also unexpectedly renders cells more likely to incur mutations and evolve resistance to antifungal agents. We further find that deletion ofREV1leads to a significant depletion in the uncharacterized protein Shm1, which itself plays a role in fungal mutagenesis. Together, this work lends new insight into previously uncharacterized factors with important roles in the DNA damage response, mutagenesis, and the evolution of antifungal drug resistance.

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“…Of interest, recent studies have confirmed the important role of REV1 in DNA damage repair and the maintenance of genomic stability. In saccharomyces cerevisiae, cells lacking REV1 are sensitive to DNA damage agents, including cisplatin, mitomycin C and UV radiation [ 7 ]. Similarly, REV1 was found to play an important role in the activation of the ATR-Chk1 checkpoint during mitomycin C-induced interstrand crosslink repair in African clawed toad egg extracts [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…Elevated REV1 expression enhances cellular tolerance to UV damage. High levels of REV1 can increase the frequency of gene mutations in cells, thus helping them to adapt to environmental stress [ 7 , 9 , 10 ]. Radiotherapy is a cytotoxic therapy that exerts its therapeutic effect mainly by inducing double-stranded DNA breaks in tumor cells, and DNA damage repair is an important factor affecting tumor radiosensitivity [ 2 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

USP9X-mediated REV1 deubiquitination promotes lung cancer radioresistance via the action of REV1 as a Rad18 molecular scaffold for cystathionine γ-lyase

Chen,

Feng,

et al. 2024

J Biomed Sci

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Background Radioresistance is a key clinical constraint on the efficacy of radiotherapy in lung cancer patients. REV1 DNA directed polymerase (REV1) plays an important role in repairing DNA damage and maintaining genomic stability. However, its role in the resistance to radiotherapy in lung cancer is not clear. This study aims to clarify the role of REV1 in lung cancer radioresistance, identify the intrinsic mechanisms involved, and provide a theoretical basis for the clinical translation of this new target for lung cancer treatment. Methods The effect of targeting REV1 on the radiosensitivity was verified by in vivo and in vitro experiments. RNA sequencing (RNA-seq) combined with nontargeted metabolomics analysis was used to explore the downstream targets of REV1. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to quantify the content of specific amino acids. The coimmunoprecipitation (co-IP) and GST pull-down assays were used to validate the interaction between proteins. A ubiquitination library screening system was constructed to investigate the regulatory proteins upstream of REV1. Results Targeting REV1 could enhance the radiosensitivity in vivo, while this effect was not obvious in vitro. RNA sequencing combined with nontargeted metabolomics revealed that the difference result was related to metabolism, and that the expression of glycine, serine, and threonine (Gly/Ser/Thr) metabolism signaling pathways was downregulated following REV1 knockdown. LC-MS/MS demonstrated that REV1 knockdown results in reduced levels of these three amino acids and that cystathionine γ-lyase (CTH) was the key to its function. REV1 enhances the interaction of CTH with the E3 ubiquitin ligase Rad18 and promotes ubiquitination degradation of CTH by Rad18. Screening of the ubiquitination compound library revealed that the ubiquitin-specific peptidase 9 X-linked (USP9X) is the upstream regulatory protein of REV1 by the ubiquitin-proteasome system, which remodels the intracellular Gly/Ser/Thr metabolism. Conclusion USP9X mediates the deubiquitination of REV1, and aberrantly expressed REV1 acts as a scaffolding protein to assist Rad18 in interacting with CTH, promoting the ubiquitination and degradation of CTH and inducing remodeling of the Gly/Ser/Thr metabolism, which leads to radioresistance. A novel inhibitor of REV1, JH-RE-06, was shown to enhance lung cancer cell radiosensitivity, with good prospects for clinical translation.

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Sml1 Inhibits the DNA Repair Activity of Rev1 in Saccharomyces cerevisiae during Oxidative Stress

Cited by 6 publications

References 51 publications

Reactive Oxygen Species Bridge the Gap between Chronic Inflammation and Tumor Development

Reactive Oxygen Species Bridge the Gap between Chronic Inflammation and Tumor Development

A role for the putative error-prone polymeraseREV1in DNA damage and antifungal drug resistance inCandida albicans

USP9X-mediated REV1 deubiquitination promotes lung cancer radioresistance via the action of REV1 as a Rad18 molecular scaffold for cystathionine γ-lyase

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