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Nucleic Acids Res. 2018 Nov 20. doi: 10.1093/nar/gky1152. [Epub ahead of print]

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.

Author information

1
Department of Molecular Medicine and Medical Biotechnologies, University of Naples 'Federico II', Naples, Italy.
2
Interuniversity Consortium for Super Computing CINECA, Rome, Italy.
3
Department of Chemical Sciences, University of Naples 'Federico II', Naples, Italy.
4
CEINGE Biotecnologie Avanzate, Naples, Italy.
5
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.
6
Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
7
Department of Oncology and Hemato-oncology, University of Milano, Milan, Italy.
8
Department of Biology, University of Naples 'Federico II', Naples, Italy.

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 ╬│H2AX 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.

PMID:
30462294
DOI:
10.1093/nar/gky1152

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