ニシ　リョウタロウ   西　良太郎    所属   応用生物学部 応用生物学科    職種   准教授
言語種別	英語
発行・発表の年月	2022/07
形態種別	学術論文
査読	査読あり
標題	USP49 is a novel deubiquitylating enzyme for gH2AX in DNA double-strand break repair
執筆形態	共著
掲載誌名	Gene
掲載区分	国外
出版社・発行元	ELSEVIER
巻・号・頁	833,pp.146599
総ページ数	9
担当区分	最終著者,責任著者
著者・共著者	Misaki Matsui, Shoki Kajita, Yuina Tsuchiya, Wakana Torii, Shiori Tamekuni and Ryotaro Nishi
概要	DNA double-strand break (DSB) that is one of the most serious DNA lesions is mainly repaired by two mutually exclusive pathways, homologous recombination and non-homologous end-joining. Proper choice of DSB repair pathway, in which recruitment of 53BP1 to chromatin around DSB sites plays a pivotal role, is crucial for maintaining genome integrity. Ubiquitylations of histone H2A and H2AX on Lys15 are prerequisite for 53BP1 loading onto chromatin. Although ubiquitylation mechanism of H2A and H2AX had been extensively studied, mechanism regulating deubiquitylation of gH2AX that is a phosphorylated form of H2AX remains elusive. Here, we identified USP49 as a novel deubiquitylating enzyme targeting DSB-induced gH2AX ubiquitylation. Over-expressed USP49 suppressed ubiquitylation of gH2AX in an enzymatic activity-dependent manner. Catalytic dead mutant of USP49 interacted and colocalized with gH2AX. Consequently, over-expression of USP49 inhibited the DSB-induced foci formation of 53BP1 and resulted in higher cell sensitivity to DSB-inducing drug treatment. Furthermore, endogenous USP49 protein was degraded via the proteasome upon DSB induction, indicating the importance of modulating USP49 protein level for gH2AX deubiquitylation. Consistent with our cell-based data, kidney renal clear cell carcinoma patients with higher expression of USP49 showed poor survival rate in comparison to the patients with unaltered USP49 expression. In conclusion, these data suggest that fine tuning of protein level of USP49 and USP49-mediated deubiquitylation of gH2AX are important for genome integrity.
DOI	10.1016/j.gene.2022.146599
論文（査読付）ファイル	DOWNLOAD