@article{cc0a0427aac2462c9c833961c3a5a0e6,
title = "UBC13-Mediated Ubiquitin Signaling Promotes Removal of Blocking Adducts from DNA Double-Strand Breaks",
abstract = "Chemical modifications and adducts at DNA double-strand break (DSB) ends must be cleaned before re-joining by non-homologous end-joining (NHEJ). MRE11 nuclease is essential for efficient removal of Topoisomerase II (TOP2)-DNA adducts from TOP2 poison-induced DSBs. However, mechanisms in MRE11 recruitment to DSB sites in G1 phase remain poorly understood. Here, we report that TOP2-DNA adducts are expeditiously removed through UBC13-mediated polyubiquitination, which promotes DSB resection in G2 phase. We found that this ubiquitin signaling is required for efficient recruitment of MRE11 onto DSB sites in G1 by facilitating localization of RAP80 and BRCA1 to DSB sites and complex formation between BRCA1 and MRE11 at DSB sites. UBC13 and MRE11 are dispensable for restriction-enzyme-induced “clean” DSBs repair but responsible for over 50% and 70% of NHEJ-dependent repair of γ-ray-induced “dirty” DSBs, respectively. In conclusion, ubiquitin signaling promotes nucleolytic removal of DSB blocking adducts by MRE11 before NHEJ.",
keywords = "Biological Sciences, Cell Biology, Molecular Biology",
author = "Remi Akagawa and Trinh, {Hai Thanh} and Saha, {Liton Kumar} and Masataka Tsuda and Kouji Hirota and Shintaro Yamada and Atsushi Shibata and Kanemaki, {Masato T.} and Shinichiro Nakada and Shunichi Takeda and Hiroyuki Sasanuma",
note = "Funding Information: We thank Dr. Junji Itou for making boxplots in R language and technical assistance. We thank Drs. Tanya T. Paull, Rajashree A. Deshpande, Penny A. Jeggo, and the members of the Radiation Genetics lab for their helpful comments on the manuscript. For technical assistance with the cell sorter and confocal microscope, we are grateful to the staff of the Medical Research Support Center (supported by Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS), AMED Grant JP19am0101092 ). This study was conducted through the Joint Research Program of the Radiation Biology Center, Kyoto University. This work was supported by JSPS KAKENHI Grant Number 23221005 and JP16H06306 (S.T.) and 16H02953 , 18H04900 , and JP19H04267 (H.S.). This study was supported by JSPS Core-to-Core Program. This work was also supported by grants from the Takeda Research and Mitsubishi Foundation (to H.S.) Publisher Copyright: {\textcopyright} 2020 The Author(s)",
year = "2020",
month = apr,
day = "24",
doi = "10.1016/j.isci.2020.101027",
language = "English",
volume = "23",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
number = "4",
}