@article{e07acb556c62476689024f3826957112,
title = "Endogenous DNA 3' Blocks Are Vulnerabilities for BRCA1 and BRCA2 Deficiency and Are Reversed by the APE2 Nuclease",
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.",
keywords = "BRCA1, BRCA2, APE2, APEX2, RNASEH2, synthetic lethality, TOP1, TDP1, ribonucleotide",
author = "Alejandro {\'A}lvarez-Quil{\'o}n and Wojtaszek, {Jessica L.} and Marie-Claude Mathieu and Tejas Patel and Appel, {C. Denise} and Nicole Hustedt and Rossi, {Silvia Emma} and Wallace, {Bret D.} and Dheva Setiaputra and Salom{\'e} Adam and Yota Ohashi and Henrique Melo and Tiffany Cho and Christian Gervais and Mu{\~n}oz, {Ivan M.} and Eric Grazzini and Young, {Jordan T. F.} and John Rouse and Michael Zinda and Williams, {R. Scott} and Daniel Durocher",
note = "We also thank K. Chan at the NBCC (LTRI) for sequencing. A.A.-Q. is a recipient of a long-term EMBO fellowship, D.S. was supported by a CIHR fellowship, and S.A. was a Banting post-doctoral fellow. Research in the R.S.W. laboratory was supported by National Institutes of Health Intramural Program, National Institute of Environmental Health Sciences (NIEHS) 1Z01ES102765. We thank L. Pedersen of the NIEHS Collaborative crystallography group for data collection support. X-ray data were collected at Southeast Regional Collaborative Access Team (SER-CAT) 22-ID beamline at the Advanced Photon Source, Argonne National Laboratory. SER-CAT is supported by its member institutions equipment grants (S10_RR25528 and S10_RR028976) from the National Institutes of Health. Use of the APS was supported by the Department of Energy, Office of Science, Office of Basic Energy Sciences under contract W-31-109-Eng-38. D.D. is a Canada Research Chair (Tier I), and work in the D.D. lab was supported by grants from the CIHR (FDN143343) and Canadian Cancer Society (705644) with additional support from the Krembil Foundation and Repare Therapeutics.",
year = "2020",
month = jun,
day = "18",
doi = "10.1016/j.molcel.2020.05.021",
language = "English",
volume = "78",
pages = "1152--1165.e8",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Elsevier",
number = "6",
}
