APOBEC3B-Mediated Cytidine Deamination Is Required for Estrogen Receptor Action in Breast Cancer

Manikandan Periyasamy, Hetal Patel, Chun Fui Lai, Van T.M. Nguyen, Ekaterina Nevedomskaya, Alison Harrod, Roslin Russell, Judit Remenyi, Anna Maria Ochocka, Ross S. Thomas, Frances Fuller-Pace, Balázs Gyorffy, Carlos Caldas, Naveenan Navaratnam, Jason S. Carroll, Wilbert Zwart, R. Charles Coombes, Luca Magnani, Laki Buluwela, Simak Ali

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Abstract

Estrogen receptor α (ERα) is the key transcriptional driver in a large proportion of breast cancers. We report that APOBEC3B (A3B) is required for regulation of gene expression by ER and acts by causing C-to-U deamination at ER binding regions. We show that these C-to-U changes lead to the generation of DNA strand breaks through activation of base excision repair (BER) and to repair by non-homologous end-joining (NHEJ) pathways. We provide evidence that transient cytidine deamination by A3B aids chromatin modification and remodelling at the regulatory regions of ER target genes that promotes their expression. A3B expression is associated with poor patient survival in ER+ breast cancer, reinforcing the physiological significance of A3B for ER action.

Original languageEnglish
Pages (from-to)108-121
Number of pages14
JournalCell Reports
Volume13
Issue number1
DOIs
Publication statusPublished - Oct 6 2015

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Periyasamy, M., Patel, H., Lai, C. F., Nguyen, V. T. M., Nevedomskaya, E., Harrod, A., Russell, R., Remenyi, J., Ochocka, A. M., Thomas, R. S., Fuller-Pace, F., Gyorffy, B., Caldas, C., Navaratnam, N., Carroll, J. S., Zwart, W., Coombes, R. C., Magnani, L., Buluwela, L., & Ali, S. (2015). APOBEC3B-Mediated Cytidine Deamination Is Required for Estrogen Receptor Action in Breast Cancer. Cell Reports, 13(1), 108-121. https://doi.org/10.1016/j.celrep.2015.08.066