title: Unpredicted Downregulation of RAD51 Suggests Genome Instability Induced by Tetrachlorobenzoquinone.
abstract: We previously demonstrated that halogenated quinone induces DNA double strand breaks (DSBs) in a ROS-dependent manner, which coordinates with downstream repair cascade including nonhomologous end joining, base excision repair, and nucleotide excision repair. However, these error-prone processes may cause the potential risk of genome instability, and current has no information on how faithful repair route, such as homologous recombination (HR), was affected. RAD51 is a key protein in the HR pathway of DSBs repair. Here, we found that tetrachlorobenzoquinone (TCBQ) causes a time-dependent reverse U-shape biphasic trend of RAD51 expression. An increase in the early stage and a following decrease of RAD51 expression were found in both 12.5 and 25 μM TCBQ groups, wherein higher concentration faced a faster response. The upregulated RAD51 in the early phase suggested the attempting to repair TCBQ-induced DNA damage; however, the downregulation of RAD51 in the late phase implicated that the rescue probably be abandoned with severe DNA damage. This phenomenon is a general toxic manner of TCBQ regardless of cell type. Surprisingly, TCBQ showed minimum effect on RAD51 mRNA (or protein) synthesis as well as RAD51 degradation. Specific inhibition of RAD51 by siRNA amplified TCBQ-induced DNA damage and cytotoxicity, while cells with enhanced RAD51 expression resisted TCBQ-induced toxicity. The modulation of RAD51 is correlated with p53 level, which suggests p53 has a role in TCBQ-induced RAD51 clearance. Together, our data suggested that TCBQ increases genome instability and cell death through a unique mechanism of inducing DNA damage and inhibiting DNA repair.
authors.affiliation: Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University , Chongqing 400715, People's Republic of China.
authors.forename: Xiufang
authors.initials: X
authors.lastname: Song
authors.affiliation: Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University , Chongqing 400715, People's Republic of China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University , Chongqing 400715, People's Republic of China.
authors.forename: Zixuan
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University , Chongqing 400715, People's Republic of China.
authors.forename: Yawen
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University , Chongqing 400715, People's Republic of China.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University , Chongqing 400715, People's Republic of China.
authors.forename: Erqun
authors.initials: E
authors.lastname: Song
authors.affiliation: Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University , Chongqing 400715, People's Republic of China.
authors.forename: Yang
authors.identifier: 0000-0001-7716-9216
authors.initials: Y
authors.lastname: Song
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004249:DNA Damage; D015536:Down-Regulation / Q000187:drug effects*; D042822:Genomic Instability / Q000187:drug effects*; D006801:Humans; D006843:Hydrocarbons, Chlorinated / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D016227:Benzoquinones; D006843:Hydrocarbons, Chlorinated; D012333:RNA, Messenger; C000591600:tetrachlorobenzoquinone; D051135:Rad51 Recombinase