Arsenite Binds to the Zinc Finger Motif of TIP60 Histone Acetyltransferase and Induces Its Degradation via the 26S Proteasome

Abstract

Arsenic is a ubiquitous environmental contaminant with widespread public health concern. Epidemiological studies have revealed that chronic human exposure to arsenic in drinking water is associated with the prevalence of skin, lung, and bladder cancers. Aberrant histone modifications (e.g., methylation, acetylation, and ubiquitination) were previously found to be accompanied by arsenic exposure; thus, perturbation of epigenetic pathways is thought to contribute to arsenic carcinogenesis. Arsenite is known to interact with zinc finger motifs of proteins, and zinc finger motif is present in and indispensable for the enzymatic activities of crucial histone-modifying enzymes especially the MYST family of histone acetyltransferases (e.g., TIP60). Hence, we reasoned that trivalent arsenic may target the zinc finger motif of these enzymes, disturb their enzymatic activities, and alter histone acetylation. Herein, we found that As3+ could bind directly to the zinc-finger motif of TIP60 in vitro and in cells. In addition, exposure to As3+ could lead to a dose-dependent decrease in TIP60 protein level via the ubiquitin-proteasome pathway. Thus, the results from the present study revealed, for the first time, that arsenite may target cysteine residues in the zinc-finger motif of the TIP60 histone acetyltransferase, thereby altering the H4K16Ac histone epigenetic mark. Our results also shed some new light on the mechanisms underlying the arsenic-induced epigenotoxicity and carcinogenesis in humans.

Arsenite Binds to ZNF598 to Perturb Ribosome-Associated Protein Quality Control

“…In light of the previous observations about the effects of As(III) binding on modulating the E3 ubiquitin ligase activities of other RING finger proteins, [20][21][22]25 we reasoned that the decreases in ubiquitination of RPS10 and RPS20 may be attributed to the interaction between As(III) and ZNF598 and the ensuing loss of its E3 ubiquitin ligase activity. To test this, we first examined the interaction between As(III) and ZNF598.…”

Arsenite Targets the RING Finger Domain of Rbx1 E3 Ubiquitin Ligase to Inhibit Proteasome-Mediated Degradation of Nrf2

“…The procedures for monitoring the interaction between the RING finger peptide of Rbx1 and As(III) were previously described. 12 Briefly, the RING-finger peptide derived from Rbx1 (VDNCAICRNAFHFHCISR) was synthesized by Genemed Synthesis Inc. (San Antonio, TX), dissolved in 50% acetonitrile, and used for the in vitro binding assays. Aliquots of 100 μM peptide were mixed with 200 μM NaAsO 2 and 100 μM dithiothreitol (DTT) and incubated on ice for 1 h. The solution was subsequently mixed with an equal volume of 2,5-dihydroxybenzoic acid matrix solution and spotted onto a sample plate.…”

“…10,11 Our previous work also elucidated the interaction between arsenite and the zinc finger motifs of Tip60 histone acetyltransferase and ten-eleven translocation (Tet) family proteins, which perturbs histone and DNA epigenetic marks. 12,13…”

Pyrrolidine Dithiocarbamate Facilitates Arsenic Trioxide Against Pancreatic Cancer via Perturbing Ubiquitin-Proteasome Pathway

“… 7 Among the E3 family, the majority of identified members contain a RING-finger domain with zinc sites where is conceived of as the target of arsenite treatment. 12 , 31 , 33 , 34 Human Pirh2 contains a RING-H2 domain, charactered by a consensus sequence with six cysteine and two histidine residues that coordinate two zinc ions, besides, there is a CHY-zinc-finger domain conjugated to the RING finger ( Figure 6B ). As an E3 ubiquitin ligase being deregulated in various cancers, Pirh2 is considered an anticancer target of arsenite therapy due to the binding of arsenic ions like their action on PML-RARα.…”