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

Par Conseil national de recherches du Canada

DOI	Trouver le DOI : https://doi.org/10.1016/j.molcel.2020.05.021
Auteur	Rechercher : Álvarez-Quilón, Alejandro; Rechercher : Wojtaszek, Jessica L.; Rechercher : Mathieu, Marie-Claude; Rechercher : Patel, Tejas; Rechercher : Appel, C. Denise; Rechercher : Hustedt, Nicole; Rechercher : Rossi, Silvia Emma; Rechercher : Wallace, Bret D.; Rechercher : Setiaputra, Dheva; Rechercher : Adam, Salomé; Rechercher : Ohashi, Yota; Rechercher : Melo, Henrique; Rechercher : Cho, Tiffany; Rechercher : Gervais, Christian¹; Rechercher : Muñoz, Ivan M.; Rechercher : Grazzini, Eric; Rechercher : Young, Jordan T.F.; Rechercher : Rouse, John; Rechercher : Zinda, Michael; Rechercher : Williams, R. Scott; Rechercher : Durocher, Daniel Identifiant ORCID : https://orcid.org/0000-0003-3863-8635
Affiliation	Conseil national de recherches du Canada. Thérapeutique en santé humaine
Format	Texte, Article
Sujet	BRCA1; BRCA2; APE2; APEX2; RNASEH2; synthetic lethality; TOP1; TDP1; ribonucleotide
Résumé	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.
Date de publication	2020-06-08
Maison d’édition	Elsevier
Dans	Molecular Cell 78, nº 6 : 1152–1165.e8.
Langue	anglais
Publications évaluées par des pairs	Oui
Identificateur	S1097276520303415
Exporter la notice	Exporter en format RIS
Signaler une correction	Signaler une correction (s'ouvre dans un nouvel onglet)
Identificateur de l’enregistrement	8f524542-7b87-4e6a-8961-c49ff004f3f3
Enregistrement créé	2020-06-26
Enregistrement modifié	2020-06-29

Date de modification :: 2024-04-26