Endogenous DNA 3′ blocks are vulnerabilities for BRCA1 and BRCA2 deficiency and are reversed by the APE2 nuclease

From National Research Council Canada

DOI	Resolve DOI: https://doi.org/10.1016/j.molcel.2020.05.021
Author	Search for: Álvarez-Quilón, Alejandro; Search for: Wojtaszek, Jessica L.; Search for: Mathieu, Marie-Claude; Search for: Patel, Tejas; Search for: Appel, C. Denise; Search for: Hustedt, Nicole; Search for: Rossi, Silvia Emma; Search for: Wallace, Bret D.; Search for: Setiaputra, Dheva; Search for: Adam, Salomé; Search for: Ohashi, Yota; Search for: Melo, Henrique; Search for: Cho, Tiffany; Search for: Gervais, Christian¹; Search for: Muñoz, Ivan M.; Search for: Grazzini, Eric; Search for: Young, Jordan T.F.; Search for: Rouse, John; Search for: Zinda, Michael; Search for: Williams, R. Scott; Search for: Durocher, Daniel ORCID identifier: https://orcid.org/0000-0003-3863-8635
Affiliation	National Research Council of Canada. Human Health Therapeutics
Format	Text, Article
Subject	BRCA1; BRCA2; APE2; APEX2; RNASEH2; synthetic lethality; TOP1; TDP1; ribonucleotide
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.
Publication date	2020-06-08
Publisher	Elsevier
In	Molecular Cell 78, no. 6: 1152–1165.e8.
Language	English
Peer reviewed	Yes
Identifier	S1097276520303415
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Record identifier	8f524542-7b87-4e6a-8961-c49ff004f3f3
Record created	2020-06-26
Record modified	2020-06-29

Date modified:: 2024-07-19