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Oxidative DNA Damage Modulates DNA Methylation Pattern in Human Breast Cancer 1 (BRCA1) Gene via the Crosstalk between DNA Polymerase β and a de novo DNA Methyltransferase

1
Biochemistry Ph.D. Program, Florida International University, Miami, FL 33199, USA
2
Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, USA
3
Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
4
Department of Biomedical Engineering, Florida International University, Miami, FL 33199, USA
5
Biomolecular Sciences Institute, Florida International University, Miami, FL 33199, USA
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Department of Human and Molecular Genetics, Florida International University, Miami, FL 33199, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to the work.
Current address: National Institute of Allergy and Infectious Diseases/National Institutes of Health, Bethesda, MD 20852, USA.
§
Current address: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Cells 2020, 9(1), 225; https://doi.org/10.3390/cells9010225 (registering DOI)
Received: 8 November 2019 / Revised: 15 December 2019 / Accepted: 13 January 2020 / Published: 16 January 2020
DNA damage and base excision repair (BER) are actively involved in the modulation of DNA methylation and demethylation. However, the underlying molecular mechanisms remain unclear. In this study, we seek to understand the mechanisms by exploring the effects of oxidative DNA damage on the DNA methylation pattern of the tumor suppressor breast cancer 1 (BRCA1) gene in the human embryonic kidney (HEK) HEK293H cells. We found that oxidative DNA damage simultaneously induced DNA demethylation and generation of new methylation sites at the CpGs located at the promoter and transcribed regions of the gene ranging from −189 to +27 in human cells. We demonstrated that DNA damage-induced demethylation was mediated by nucleotide misincorporation by DNA polymerase β (pol β). Surprisingly, we found that the generation of new DNA methylation sites was mediated by coordination between pol β and the de novo DNA methyltransferase, DNA methyltransferase 3b (DNMT3b), through the interaction between the two enzymes in the promoter and encoding regions of the BRCA1 gene. Our study provides the first evidence that oxidative DNA damage can cause dynamic changes in DNA methylation in the BRCA1 gene through the crosstalk between BER and de novo DNA methylation. View Full-Text
Keywords: oxidative DNA damage; DNA polymerase β; DNA methyltransferase 3b; BRCA1; base excision repair; DNA methylation; de novo DNA methylation oxidative DNA damage; DNA polymerase β; DNA methyltransferase 3b; BRCA1; base excision repair; DNA methylation; de novo DNA methylation
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Jiang, Z.; Lai, Y.; Beaver, J.M.; Tsegay, P.S.; Zhao, M.-L.; Horton, J.K.; Zamora, M.; Rein, H.L.; Miralles, F.; Shaver, M.; Hutcheson, J.D.; Agoulnik, I.; Wilson, S.H.; Liu, Y. Oxidative DNA Damage Modulates DNA Methylation Pattern in Human Breast Cancer 1 (BRCA1) Gene via the Crosstalk between DNA Polymerase β and a de novo DNA Methyltransferase. Cells 2020, 9, 225.

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