Repair of UV-Induced DNA Damage Independent of Nucleotide Excision Repair Is Masked by MUTYH

Mazouzi, Abdelghani; Battistini, Federica; Moser, Sarah C.; Silva, Joana Ferreira da; Wiedner, Marc; Owusu, Michel; Lardeau, Charles-Hugues; Ringler, Anna; Weil, Beatrix; Neesen, Jürgen; Orozco, Modesto; Kubicek, Stefan; Loizou, Joanna I.

doi:10.1016/j.molcel.2017.10.021

Cited by 33 publications

(33 citation statements)

References 42 publications

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“…To gain insights into how TM-induced DNA damage is sensed and repaired in host cells, we next asked whether mutation of genes encoding key repair factors would render cells hypersensitive to TM. Inactivating mutations were generated in the human haploid cell line HAP1 (32, 33). Equal numbers of cells for each mutant line were cultured with increasing concentrations of TM, TV, or controls, and cell viability was measured (Fig.…”

Section: Resultsmentioning

confidence: 99%

Klebsiella oxytoca enterotoxins tilimycin and tilivalline have distinct host DNA-damaging and microtubule-stabilizing activities

Unterhauser

Pöltl

Schneditz

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Establishing causal links between bacterial metabolites and human intestinal disease is a significant challenge. This study reveals the molecular basis of antibiotic-associated hemorrhagic colitis (AAHC) caused by intestinal resident Klebsiella oxytoca. Colitogenic strains produce the nonribosomal peptides tilivalline and tilimycin. Here, we verify that these enterotoxins are present in the human intestine during active colitis and determine their concentrations in a murine disease model. Although both toxins share a pyrrolobenzodiazepine structure, they have distinct molecular targets. Tilimycin acts as a genotoxin. Its interaction with DNA activates damage repair mechanisms in cultured cells and causes DNA strand breakage and an increased lesion burden in cecal enterocytes of colonized mice. In contrast, tilivalline binds tubulin and stabilizes microtubules leading to mitotic arrest. To our knowledge, this activity is unique for microbiota-derived metabolites of the human intestine. The capacity of both toxins to induce apoptosis in intestinal epithelial cells—a hallmark feature of AAHC—by independent modes of action, strengthens our proposal that these metabolites act collectively in the pathogenicity of colitis.

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Section: Resultsmentioning

confidence: 99%

Klebsiella oxytoca enterotoxins tilimycin and tilivalline have distinct host DNA-damaging and microtubule-stabilizing activities

Unterhauser

Pöltl

Schneditz

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…UV‐induced DNA lesions have been thought to be repaired solely by NER. However, a recent study demonstrated the existence of an NER‐independent repair mechanism for removing UV‐induced DNA damage in human cells (116). An antidiabetic drug, acetohexamide, was recently identified as an agent that alleviates the UV sensitivity of NER‐deficient cells.…”

Section: Updated Models Of Uv‐induced Dna Damage Responsesmentioning

confidence: 99%

Deciphering UV‐induced DNA Damage Responses to Prevent and Treat Skin Cancer

Lee

Ratnakumar

Hung

et al. 2020

Photochem & Photobiology

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Ultraviolet (UV) radiation is among the most prevalent environmental factors that influence human health and disease. Even 1 h of UV irradiation extensively damages the genome. To cope with resulting deleterious DNA lesions, cells activate a multitude of DNA damage response pathways, including DNA repair. Strikingly, UV‐induced DNA damage formation and repair are affected by chromatin state. When cells enter S phase with these lesions, a distinct mutation signature is created via error‐prone translesion synthesis. Chronic UV exposure leads to high mutation burden in skin and consequently the development of skin cancer, the most common cancer in the United States. Intriguingly, UV‐induced oxidative stress has opposing effects on carcinogenesis. Elucidating the molecular mechanisms of UV‐induced DNA damage responses will be useful for preventing and treating skin cancer with greater precision. Excitingly, recent studies have uncovered substantial depth of novel findings regarding the molecular and cellular consequences of UV irradiation. In this review, we will discuss updated mechanisms of UV‐induced DNA damage responses including the ATR pathway, which maintains genome integrity following UV irradiation. We will also present current strategies for preventing and treating nonmelanoma skin cancer, including ATR pathway inhibition for prevention and photodynamic therapy for treatment.

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“…Chemical screens have been used for decades to assess the toxicity of drugs, and the development of high-throughput readouts now allow for the analysis of bigger libraries comprising hundreds to thousands of compounds [197,198]. For instance, screening of a chemical library allowed the identification of a potent inhibitor of a mutated form of isocitrate dehydrogenase 2 (IDH2), which is expressed in acute myelogenous leukemia, and which is now used as a chemotherapeutic [199].…”

Section: Outlook: Approaches To Identify Interactions Between Metabolmentioning

confidence: 99%

Interplay between Cellular Metabolism and the DNA Damage Response in Cancer

Moretton

Loizou

2020

Cancers

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Metabolism is a fundamental cellular process that can become harmful for cells by leading to DNA damage, for instance by an increase in oxidative stress or through the generation of toxic byproducts. To deal with such insults, cells have evolved sophisticated DNA damage response (DDR) pathways that allow for the maintenance of genome integrity. Recent years have seen remarkable progress in our understanding of the diverse DDR mechanisms, and, through such work, it has emerged that cellular metabolic regulation not only generates DNA damage but also impacts on DNA repair. Cancer cells show an alteration of the DDR coupled with modifications in cellular metabolism, further emphasizing links between these two fundamental processes. Taken together, these compelling findings indicate that metabolic enzymes and metabolites represent a key group of factors within the DDR. Here, we will compile the current knowledge on the dynamic interplay between metabolic factors and the DDR, with a specific focus on cancer. We will also discuss how recently developed high-throughput technologies allow for the identification of novel crosstalk between the DDR and metabolism, which is of crucial importance to better design efficient cancer treatments.

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Repair of UV-Induced DNA Damage Independent of Nucleotide Excision Repair Is Masked by MUTYH

Cited by 33 publications

References 42 publications

Klebsiella oxytoca enterotoxins tilimycin and tilivalline have distinct host DNA-damaging and microtubule-stabilizing activities

Klebsiella oxytoca enterotoxins tilimycin and tilivalline have distinct host DNA-damaging and microtubule-stabilizing activities

Deciphering UV‐induced DNA Damage Responses to Prevent and Treat Skin Cancer

Interplay between Cellular Metabolism and the DNA Damage Response in Cancer

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