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

• Published in: Molecular cell Vol. 78; no. 6; pp. 1152 - 1165.e8
• Main Authors: Álvarez-Quilón, Alejandro, Wojtaszek, Jessica L., Mathieu, Marie-Claude, Patel, Tejas, Appel, C. Denise, Hustedt, Nicole, Rossi, Silvia Emma, Wallace, Bret D., Setiaputra, Dheva, Adam, Salomé, Ohashi, Yota, Melo, Henrique, Cho, Tiffany, Gervais, Christian, Muñoz, Ivan M., Grazzini, Eric, Young, Jordan T.F., Rouse, John, Zinda, Michael, Williams, R. Scott, Durocher, Daniel
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.06.2020; Elsevier
• Subjects: APE2; APEX2; BRCA1; BRCA1 Protein - genetics; BRCA1 Protein - metabolism; BRCA2; BRCA2 Protein - genetics; BRCA2 Protein - metabolism; Cell Line; DNA - metabolism; DNA Damage; DNA Repair - genetics; DNA-(Apurinic or Apyrimidinic Site) Lyase - genetics; DNA-(Apurinic or Apyrimidinic Site) Lyase - metabolism; Endonucleases - genetics; Endonucleases - metabolism; Genes, BRCA1 - physiology; Humans; Multifunctional Enzymes - genetics; Multifunctional Enzymes - metabolism; Phosphoric Diester Hydrolases - genetics; Phosphoric Diester Hydrolases - metabolism; ribonucleotide; RNASEH2; synthetic lethality; TDP1; TOP1; APE2; RNASEH2; TDP1; ribonucleotide; synthetic lethality; APEX2; BRCA1; TOP1; BRCA2
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2020.05.021

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. [Display omitted] •Loss of APE2 is lethal in cells with mutations in BRCA1 or BRCA2•The APE2 DNA repair nuclease removes endogenous DNA 3′ blocks•3′ blocks arising from ribonucleotides cause APEX2-BRCA1/2 synthetic lethality•DNA 3′ block-resolving pathways are vulnerabilities for HR-deficient tumor cells Álvarez-Quilón and Wojtaszek et al. propose that APE2 is the main human enzyme reverting endogenous DNA 3′ blocks, problematic lesions that preclude DNA synthesis. TOP1 conversion of genomic ribonucleotides into 3′-blocked lesions underlies APEX2-BRCA1/2 synthetic lethality. 3′-adducted DNA damage represents a tractable vulnerability in HR-deficient tumor cells.