Endogenous DNA 3' Blocks Are Vulnerabilities for BRCA1 and BRCA2 Deficiency and Are Reversed by the APE2 Nuclease

Alejandro Álvarez-Quilón, Jessica L. Wojtaszek, Marie-Claude Mathieu, Tejas Patel, C. Denise Appel, Nicole Hustedt, Silvia Emma Rossi, Bret D. Wallace, Dheva Setiaputra, Salomé Adam, Yota Ohashi, Henrique Melo, Tiffany Cho, Christian Gervais, Ivan M. Muñoz, Eric Grazzini, Jordan T. F. Young, John Rouse, Michael Zinda, R. Scott Williams (Lead / Corresponding author)Daniel Durocher

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Abstract

The APEX2 gene encodes APE2, a nuclease related to APE1, the apurinic/apyrimidinic endonuclease acting in base excision repair. Loss of APE2 is lethal in cells with mutated BRCA1 or BRCA2, making APE2 a prime target for homologous recombination-defective cancers. However, because the function of APE2 in DNA repair is poorly understood, it is unclear why BRCA-deficient cells require APE2 for viability. Here we present the genetic interaction profiles of APE2, APE1, and TDP1 deficiency coupled to biochemical and structural dissection of APE2. We conclude that the main role of APE2 is to reverse blocked 3' DNA ends, problematic lesions that preclude DNA synthesis. Our work also suggests that TOP1 processing of genomic ribonucleotides is the main source of 3'-blocking lesions relevant to APEX2-BRCA1/2 synthetic lethality. The exquisite sensitivity of BRCA-deficient cells to 3' blocks indicates that they represent a tractable vulnerability in homologous recombination-deficient tumor cells.

Original languageEnglish
Pages (from-to)1152-1162.e1-e8
Number of pages23
JournalMolecular Cell
Volume78
Early online date8 Jun 2020
DOIs
Publication statusPublished - 18 Jun 2020

Keywords

  • BRCA1
  • BRCA2
  • APE2
  • APEX2
  • RNASEH2
  • synthetic lethality
  • TOP1
  • TDP1
  • ribonucleotide

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    Álvarez-Quilón, A., Wojtaszek, J. L., Mathieu, M-C., Patel, T., Appel, C. D., Hustedt, N., Rossi, S. E., Wallace, B. D., Setiaputra, D., Adam, S., Ohashi, Y., Melo, H., Cho, T., Gervais, C., Muñoz, I. M., Grazzini, E., Young, J. T. F., Rouse, J., Zinda, M., ... Durocher, D. (2020). Endogenous DNA 3' Blocks Are Vulnerabilities for BRCA1 and BRCA2 Deficiency and Are Reversed by the APE2 Nuclease. Molecular Cell, 78, 1152-1162.e1-e8. https://doi.org/10.1016/j.molcel.2020.05.021