Genome-wide mapping of 8-oxo-7,8-dihydro-2′-deoxyguanosine reveals accumulation of oxidatively-generated damage at DNA replication origins within transcribed long genes of mammalian cells

Stefano Amente, Giacomo Di Palo, Giovanni Scala, Tiziana Castrignanò, Francesca Gorini, Sergio Cocozza, Angela Moresano, Piero Pucci, Bin Ma, Irina Stepanov, Luigi Lania, Pier Giuseppe Pelicci, Gaetano Ivan Dellino, Barbara Majello

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

8-Oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) is one of the major DNA modifications and a potent pre-mutagenic lesion prone to mispair with 2′-deoxyadenosine (dA). Several thousand residues of 8-oxodG are constitutively generated in the genome of mammalian cells, but their genomic distribution has not yet been fully characterized. Here, by using OxiDIP-Seq, a highly sensitive methodology that uses immuno-precipitation with efficient anti-8-oxodG antibodies combined with high-throughput sequencing, we report the genome-wide distribution of 8-oxodG in human non-tumorigenic epithelial breast cells (MCF10A), and mouse embryonic fibroblasts (MEFs). OxiDIP-Seq revealed sites of 8-oxodG accumulation overlapping with Î 3H2AX ChIP-Seq signals within the gene body of transcribed long genes, particularly at the DNA replication origins contained therein. We propose that the presence of persistent single-stranded DNA, as a consequence of transcription-replication clashes at these sites, determines local vulnerability to DNA oxidation and/or its slow repair. This oxidatively-generated damage, likely in combination with other kinds of lesion, might contribute to the formation of DNA double strand breaks and activation of DNA damage response.

Original languageEnglish (US)
Pages (from-to)221-236
Number of pages16
JournalNucleic acids research
Volume47
Issue number1
DOIs
StatePublished - Jan 10 2019

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© 2018 The Author(s).

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