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Single Base Resolution Genome-Wide Maps of DNA Damage to Forecast Mutation Signatures

English title Single Base Resolution Genome-Wide Maps of DNA Damage to Forecast Mutation Signatures
Applicant Sturla Shana
Number 185020
Funding scheme Project funding (Div. I-III)
Research institution Institut für Lebensmittelwissenschaften, Ernährung und Gesundheit ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Biochemistry
Start/End 01.01.2020 - 31.12.2023
Approved amount 588'000.00
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All Disciplines (2)

Discipline
Biochemistry
Organic Chemistry

Keywords (12)

DNA Glycosylases; Mutagenesis; DNA Adducts; Sequencing Technology; Click Chemistry; Oxidative Stress; Cancer Prevention; Mutation Signatures; DNA oxidation damage; cancer; DNA repair; genome-wide mapping

Lay Summary (French)

Lead
Cartographier les bases d’ADN endommagées afin de prédire les motifs de mutations qui en découlent?L’intégrité de notre ADN est menacée chaque jour par des substances réactives qui peuvent endommager les bases qui constituent le code de notre information génétique. Nous sommes exposés à ces substances réactives extrinsèquement (polluants dans l’air, fumée de cigarette, lumière du soleil) et intrinsèquement (les espèces réactives de l’oxygène qui sont produites pendant la respiration cellulaire). Ces dommages sur nos bases d’ADN mènent à des mutations qui peuvent causer le cancer chez l’homme. Pour pouvoir prévenir et traiter le cancer, nous devons comprendre où et quand il commence, c’est pour cela que nous nous intéressons aux premiers changements qui sont les dommages sur l’ADN.
Lay summary

Contenu et objectifs du travail de recherche

En 2004, la séquence du génome humain a été révélée après 15 ans de travaux, aujourd’hui, grâce au progrès de la science, nous pouvons séquencer un génome en quelques jours. Notre projet veut cartographier par séquençage les dommages oxydatifs sur l’ADN causés, par exemple, par la respiration cellulaire, la lumière du soleil et certaines substances trouvées dans notre environnement et notre nourriture. Le dogme central est que certaines mutations présentes dans les cancers humains résultent des dommages oxydatifs sur l’ADN, il est donc important d’identifier les dangers pour la santé humaine, l’influence de l’architecture génomique et finalement quels sont les mécanismes de réparation que nos cellules ont développé avec le temps. Nous pensons contribuer à la découverte de nouvelles causes moléculaire impliquées dans l’initiation et le développement de cancers.

Contexte scientifique et social du projet de recherche

Le projet relève de la recherche fondamentale. Pour contrer le cancer nous devons identifier les premiers changements moléculaires.

Direct link to Lay Summary Last update: 28.06.2019

Responsible applicant and co-applicants

Employees

Project partner

Associated projects

Number Title Start Funding scheme
186332 Hijacking Transcription-Coupled DNA Repair for Cancer Therapy 01.01.2020 Sinergia

Abstract

Background and Rationale. Human cancers arise from mutations due to endogenous processes and exposure to xenobiotic chemicals. Cellular repair pathways are fantastically evolved to avoid adverse effects of DNA damage, particularly in response to the high abundance of various oxidation and methylation-derived DNA base adducts. Nonetheless, exposures to an increasing variety and amount of chemicals from the environment, diet and drugs, together with defects or deficiencies in repair, adds to risk of mutagenesis and carcinogenesis. Current understanding of how DNA oxidation and methylation drive mutagenesis is advanced, but our ability to predict the mutagenicity of chemicals or disease risks related to these processes remains limited in part because there exists a mismatch between our low resolution understanding of how DNA adducts are distributed and dynamically altered on a genome-wide level vs. our sophisticated knowledge of intricate mutational landscapes of human cancers. Systems biology-based predictive models linking chemical exposures with mutational signatures is fundamentally limited by this lack of information and methods to map DNA damage. Objectives. The long-term goal of the research program is to identify human health hazards from chemicals via in vitro systems-wide characterization of molecular responses. The objectives of this project are to map oxidation damage in mammalian cells, understand how damage maps are governed by chemical sources, repair, and genomic architecture, and relate them with in vitro mutational signatures. The central hypothesis is that oxidation-initiated mutation signatures result from pervasive DNA oxidation patterns related to the dose and chemistry of their origin, followed by damage removal by BER that biases the distribution and consequences of damage. In preliminary studies, we developed a novel method for single nucleotide mapping of oxidation damage in whole genomes, and established an in vitro strategy to determine the impact of enzymatic deficiencies on mutation signatures. The team combines expertise in the chemistry of DNA damage, bioanalysis, biochemistry, DNA repair, genome sequencing and bioinformatics, and computational biology.Aim 1. Impact of genomic architecture and DNA repair on damage signatures in mammalian genomes. Aim 2. DNA damage maps as biomarkers of oxidation-mediated toxicity initiation. Aim 3. Oxidation-induced mutagenesis. Expected Results. The anticipated results include the ready availability of new bioanalysis strategies and reagents for mapping the formation and repair of DNA damage, a strong understanding of experimental factors that bias damage sequencing results and how to interpret damage maps as a new form of data. We will gain a quantitative understanding of the relative contributions of damage chemistry, BER, and genome architecture to the biological relevance of DNA oxidation. Finally, we will establish for the first time a basis for relating the single base resolution distribution of oxidative damage in genomic DNA with mutational signatures in mutated cells.Impact. The results will stimulate the emerging field of DNA damage and repair sequencing in terms of innovative technology, companion reagents and data analysis strategies. New insights will be gained concerning DNA damage processes relevant to chemical exposures and chronic inflammation, advancing science concerning cellular oxidative processes and providing unique reference data sets for research concerning redox homeostasis and its disruption. The program will educate young scientists with interdisciplinary skills at not only the chemistry-biology interface, but with competence in quantitative and large-scale data use. Finally, there are broad future impacts to efforts to quantify risk on the basis of early biomarkers and identify causative factors of individual cancers.
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