Pervasive lesion segregation shapes cancer genome evolution
Autor: | Aitken, Sarah J., Anderson, Craig J., Connor, Frances, Pich, Oriol, Sundaram, Vasavi, Feig, Christine, Rayner, Tim F., Lukk, Margus, Aitken, Stuart, Luft, Juliet, Kentepozidou, Elissavet, Arnedo-Pac, Claudia, Beentjes, Sjoerd V., Davies, Susan E., Drews, Ruben M., Ewing, Ailith, Kaiser, Vera B., Khamseh, Ava, López-Arribillaga, Erika, Redmond, Aisling M., Santoyo-Lopez, Javier, Sentís, Inés, Talmane, Lana, Yates, Andrew D., Flicek, Paul, López-Bigas, Núria, Odom, Duncan T., Semple, Colin A., Taylor, Martin S. |
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Přispěvatelé: | Aitken, Sarah [0000-0002-1897-4140], Connor, Frances [0000-0003-2858-9411], Apollo - University of Cambridge Repository |
Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
Male
DNA Repair Transcription Genetic Cell division Genome chemistry.chemical_compound Mice 0302 clinical medicine Chromosome Segregation Neoplasms Cancer genomics Genetics 0303 health sciences Multidisciplinary Liver Neoplasms Cell cycle 3. Good health ErbB Receptors raf Kinases medicine.symptom Signal Transduction DNA Replication Tumour heterogeneity DNA repair Base pair DNA damage Sister chromatid exchange Biology Lesion Evolution Molecular 03 medical and health sciences medicine Animals Humans Allele Selection Genetic Alleles 030304 developmental biology DNA replication Cancer DNA adducts medicine.disease Nucleotide excision repair chemistry Mutation ras Proteins Sister Chromatid Exchange DNA 030217 neurology & neurosurgery |
Zdroj: | Aitken, S J, Anderson, C J, Connor, F, Pich, O, Sundaram, V, Feig, C, Rayner, T F, Lukk, M, Aitken, S, Luft, J, Kentepozidou, E, Arnedo-Pac, C, Beentjes, S V, Davies, S E, Drews, R M, Ewing, A, Kaiser, V B, Khamseh, A, Lopez-Arribillaga, E, Redmond, A M, Santoyo-Lopez, J, Sentís, I, Talmane, L, Yates, A D, Semple, C A, López-Bigas, N, Flicek, P, Odom, D T & Taylor, M S 2020, ' Pervasive lesion segregation shapes cancer genome evolution ', Nature, vol. 583, pp. 265–270 . https://doi.org/10.1038/s41586-020-2435-1 Nature |
DOI: | 10.1101/868679 |
Popis: | SummaryCancers arise through the acquisition of oncogenic mutations and grow through clonal expansion1, 2. Here we reveal that most mutagenic DNA lesions are not resolved as mutations within a single cell-cycle. Instead, DNA lesions segregate unrepaired into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations. We characterise this process in mutagen-induced mouse liver tumours and show that DNA replication across persisting lesions can generate multiple alternative alleles in successive cell divisions, thereby increasing both multi-allelic and combinatorial genetic diversity. The phasing of lesions enables the accurate measurement of strand biased repair processes, the quantification of oncogenic selection, and the fine mapping of sister chromatid exchange events. Finally, we demonstrate that lesion segregation is a unifying property of exogenous mutagens, including UV light and chemotherapy agents in human cells and tumours, which has profound implications for the evolution and adaptation of cancer genomes. |
Databáze: | OpenAIRE |
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