The SUMO-targeted ubiquitin ligase RNF4 localizes to etoposide-exposed mitotic chromosomes: Implication for a novel DNA damage response during mitosis |
| |
Authors: | Masayuki Saito Yuka Fujimitsu Takeshi Sasano Yushi Yoshikai Reiko Ban-Ishihara Yuko Nariai Takeshi Urano Hisato Saitoh |
| |
Affiliation: | 1. Department of Biological Sciences, Graduate School of Science and Technology, Kumamoto University, 2-39-1 Kurokami, Chuo-ku, Kumamoto 860-8555, Japan;2. Department of Biochemistry, Shimane University School of Medicine, 89-1 Enya-cho, Izumo 693-8501, Japan;3. Department of New Frontier Sciences, Graduate School of Science and Technology, Kumamoto University, 2-39-1 Kurokami, Chuo-ku, Kumamoto 860-8555, Japan |
| |
Abstract: | RNF4, a SUMO-targeted ubiquitin ligase (STUbL), localizes to the nucleus and functions in the DNA damage response during interphase of the cell cycle. RNF4 also exists in cells undergoing mitosis, where its regulation and function remain poorly understood. Here we showed that administration of etoposide, an anticancer DNA topoisomerase II poison, to mitotic human cervical cancer HeLa cells induced SUMO-2/3-dependent localization of RNF4 to chromosomes. The FK2 antibody signals, indicative of poly/multi-ubiquitin assembly, were detected on etoposide-exposed mitotic chromosomes, whereas the signals were negligible in cells depleted for RNF4 by RNA interference. This suggests that RNF4 functions as a STUbL in the etoposide-induced damage response during mitosis. Indeed, RNF4-depletion sensitized mitotic HeLa cells to etoposide and increased cells with micronuclei. These results indicate the importance of the RNF4-mediated STUbL pathway during mitosis for the maintenance of chromosome integrity and further implicate RNF4 as a target for topo II poison-based therapy for cancer patients. |
| |
Keywords: | Mitosis Chromosome Ring finger protein 4 (RNF4) Small ubiquitin-related modifier (SUMO)-targeted ubiquitin ligase DNA topoisomerase II Etoposide (VP-16) |
本文献已被 ScienceDirect 等数据库收录! |
|