title: Arsenite binds to the RING finger domains of RNF20-RNF40 histone E3 ubiquitin ligase and inhibits DNA double-strand break repair.
abstract: Arsenic is a widespread environmental contaminant. However, the exact molecular mechanisms underlying the carcinogenic effects of arsenic remain incompletely understood. Core histones can be ubiquitinated by RING finger E3 ubiquitin ligases, among which the RNF20-RNF40 heterodimer catalyzes the ubiquitination of histone H2B at lysine 120. This ubiquitination event is important for the formation of open and biochemically accessible chromatin fiber that is conducive for DNA repair. Herein, we found that arsenite could bind directly to the RING finger domains of RNF20 and RNF40 in vitro and in cells, and treatment with arsenite resulted in substantially impaired H2B ubiquitination in multiple cell lines. Exposure to arsenite also diminished the recruitment of BRCA1 and RAD51 to laser-induced DNA double-strand break (DSB) sites, compromised DNA DSB repair in human cells, and rendered cells sensitive toward a radiomimetic agent, neocarzinostatin. Together, the results from the present study revealed, for the first time, that arsenite may exert its carcinogenic effect by targeting cysteine residues in the RING finger domains of histone E3 ubiquitin ligase, thereby altering histone epigenetic mark and compromising DNA DSB repair. Our results also suggest arsenite as a general inhibitor for RING finger E3 ubiquitin ligases.
authors.affiliation: Department of Chemistry, §Environmental Toxicology Graduate Program, and ∥Department of Biochemistry, University of California , Riverside, California 92521, United States.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Manikandan
authors.initials: M
authors.lastname: Paramasivam
authors.forename: Qian
authors.initials: Q
authors.lastname: Cai
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Dai
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Wang
authors.forename: Krystal
authors.initials: K
authors.lastname: Lin
authors.forename: Jikui
authors.initials: J
authors.lastname: Song
authors.forename: Michael M
authors.initials: MM
authors.lastname: Seidman
authors.forename: Yinsheng
authors.initials: Y
authors.lastname: Wang
mesh_terms: D018053:Arsenites / Q000378:metabolism*; D002273:Carcinogens / Q000378:metabolism*; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D006657:Histones / Q000378:metabolism; D006801:Humans; D054829:RING Finger Domains; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D018053:Arsenites; D002273:Carcinogens; D006657:Histones; C506646:RNF20 protein, human; C413363:RNF40 protein, human; D044767:Ubiquitin-Protein Ligases; C015001:arsenite