@article{f1c36bbd9ba54c3b8066a04ccd460486,
title = "POLθ-mediated end joining is restricted by RAD52 and BRCA2 until the onset of mitosis",
abstract = "BRCA2-mutant cells are defective in homologous recombination, making them vulnerable to the inactivation of other pathways for the repair of DNA double-strand breaks (DSBs). This concept can be clinically exploited but is currently limited due to insufficient knowledge about how DSBs are repaired in the absence of BRCA2. We show that DNA polymerase θ (POLθ)-mediated end joining (TMEJ) repairs DSBs arising during the S phase in BRCA2-deficient cells only after the onset of the ensuing mitosis. This process is regulated by RAD52, whose loss causes the premature usage of TMEJ and the formation of chromosomal fusions. Purified RAD52 and BRCA2 proteins both block the DNA polymerase function of POLθ, suggesting a mechanism explaining their synthetic lethal relationships. We propose that the delay of TMEJ until mitosis ensures the conversion of originally one-ended DSBs into two-ended DSBs. Mitotic chromatin condensation might further serve to juxtapose correct break ends and limit chromosomal fusions.",
author = "Marta Llorens-Agost and Michael Ensminger and Le, {Hang Phuong} and Anugrah Gawai and Jie Liu and Andr{\'e}s Cruz-Garc{\'i}a and Sarita Bhetawal and Wood, {Richard D.} and Wolf-Dietrich Heyer and Markus L{\"o}brich",
note = "Funding Information: We thank J. Stark for providing the U2OS EJ2 reporter and POLθ/RAD52 KO cell lines, and A. L{\"o}wer and P. Jeggo for helpful discussions. We thank R. Weimer, C. Braun and M. P. Lowery for technical assistance, and D. Deckbar and A. Taubmann for experimental and intellectual contributions during the early stages of the project. Work in the M.L. laboratory is supported by the Deutsche Forschungsgemeinschaft (DFG, project ID 393547839—SFB 1361) and the Bundesministerium f{\"u}r Bildung und Forschung (grant nos 02NUK054C, 02NUK050B and 02NUK042D), work in the W.D.H. laboratory is supported by the National Institutes of Health (grant nos GM58015 and GM137751), and work in the R.D.W. laboratory is supported by the National Institutes of Health (grant nos CA247773 and CA193124) and the J. Ralph Meadows Chair in Carcinogenesis Research. This research was also supported by the National Institutes of Health award CA187561 to J.L. and by core services supported by P30 CA93373. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2021",
month = oct,
doi = "10.1038/s41556-021-00764-0",
language = "English (US)",
volume = "23",
pages = "1095--1104",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "10",
}