Perturbation of base excision repair sensitizes breast cancer cells to APOBEC3 deaminase-mediated mutations
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, United States
Abstract
Abundant APOBEC3 (A3) deaminase-mediated mutations can dominate the mutational landscape ('mutator phenotype') of some cancers, however the basis of this sporadic vulnerability is unknown. We show here that elevated expression of the bifunctional DNA glycosylase, NEIL2, sensitizes breast cancer cells to A3B-mediated mutations and double strand breaks (DSBs) by perturbing canonical base excision repair (BER). NEIL2 usurps the canonical lyase, APE1, at abasic sites in a purified BER system, rendering them poor substrates for polymerase b. However, the nicked NEIL2 product can serve as an entry site for Exo1 in vitro to generate single-stranded DNA, which would be susceptible to both A3B and DSBs. As NEIL2 or Exo1 depletion mitigates the DNA damage caused by A3B expression, we suggest that aberrant NEIL2 expression can explain certain instances of A3B-mediated mutations.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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Funding
National Institute of Diabetes and Digestive and Kidney Diseases (Intramural Research Program)
- Anthony V Furano
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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Perturbation of base excision repair sensitizes breast cancer cells to APOBEC3 deaminase-mediated mutations
eLife 9:e51605.
https://doi.org/10.7554/eLife.51605
