Chromatin accessibility of primary human cancers ties regional mutational processes with tissues of origin

Regional mutagenesis in cancer genomes associates with DNA replication timing (RT) and chromatin accessibility (CA) of normal cells, however human cancer epigenomes remain uncharacterized in this context. Here we model megabase-scale mutation frequencies in 2517 cancer genomes with 773 CA and RT profiles of cancers and normal cells. We find that CA profiles of matching cancers, rather than normal cells, predict regional mutagenesis and mutational signatures, indicating that most passenger mutations follow the epigenetic landscapes of transformed cells. Carcinogen-induced and unannotated signatures show the strongest associations with epigenomes. Associations with normal cells in melanomas, lymphomas and SBS1 signatures suggest earlier occurrence of mutations in cancer evolution. Frequently mutated regions unexplained by CA and RT are enriched in cancer genes and developmental pathways, reflecting contributions of localized mutagenesis and positive selection. These results underline the complex interplay of mutational processes, genome function and evolution in cancer and tissues of origin.

Mutants of Escherichia coli with increased fidelity of DNA replication.

To improve our understanding of the role of DNA replication fidelity in mutagenesis, we undertook a search for Escherichia coli antimutator strains with increased fidelity of DNA replication. The region between 4 and 5 min of the E. coli chromosome was mutagenized using localized mutagenesis mediated by bacteriophage P1. This region contains the dnaE and dnaQ genes, which encode, respectively, the DNA polymerase (alpha subunit) and 3' exonucleolytic proofreading activity (epsilon subunit) of DNA polymerase III holoenzyme, the enzyme primarily responsible for replicating the bacterial chromosome. The mutated bacteria were screened for antimutator phenotype in a strain defective in DNA mismatch repair (mutL), using a papillation assay based on the reversion of the galK2 mutation. In a mutL strain, mutations result primarily from DNA replication errors. Among 10,000 colonies, seven mutants were obtained whose level of papillation was reduced 5-30-fold. These mutants also displayed decreased mutation frequencies for rifampicin or nalidixic acid resistance as well as for other markers. Mapping by P1 transduction and complementation showed each to reside in dnaE. These observations support the idea that the mutants represent antimutators which replicate their DNA with increased fidelity. Mutation rates were reduced in both mutL and mutT backgrounds, but mutagenesis by ultraviolet light was not significantly affected, suggesting that the antimutator effect may be largely restricted to normal DNA replication.