Occupational and/or environmental exposure to nickel has been implicated in various types of cancer, and in vitro exposure to nickel compounds results in the accumulation of Ni(II) ions in cells. One group of major targets of Ni(II) ions inside the cell consists of Fe(II)- and αKG-dependent dioxygenases. Using JMJD2A and JMJD2C as examples, we show that the JMJD2 family of histone demethylases, which are products of putative oncogenes as well as Fe(II)- and αKG-dependent dioxygenases, are highly sensitive to inhibition by Ni(II) ions. In this work, X-ray absorption spectroscopy (XAS) has been used to investigate the Fe(II) active site of truncated JMJD2A and JMJD2C (1-350 amino acids) in the presence and absence of αKG and/or substrate to obtain mechanistic details of the early steps in catalysis that precede O2 binding in histone demethylation by the JMJD2 family of histone demethylases. Zinc K-edge XAS has been performed on the resting JMJD2A (with iron in the active site) to confirm the presence of the expected structural zinc site. XAS of the Ni(II)-substituted enzymes has also been performed to investigate the inhibition of these enzymes by Ni(II) ions. Our XAS results indicate that the five-coordinate Fe(II) center in the resting enzyme is retained in the binary and ternary complexes. In contrast, the Ni(II) center is six-coordinate in the resting enzyme and binary and ternary complexes. XAS results indicate that both Fe(II) and Ni(II) bind αKG in the binary and ternary complexes. The electron density buildup that is observed at the Fe(II) center in the presence of αKG and substrate is not observed at the Ni(II) center. Thus, both electronic and steric factors are responsible for Ni-induced inhibition of the JMJD2 family of histone demethylases. Ni-induced inhibition of these enzymes may explain the alteration of the epigenetic mechanism of gene expression that is responsible for Ni-induced carcinogenesis.
Occupational and/or envn class="Chemical">ironmental exposure to nickel has been implicated in various types of cancer, and in vitro exposure to nickel compounds results in the accumulation of Ni(II) ions in cells. One group of major targets of Ni(II) ions inside the cell consists of Fe(II)- and αKG-dependent dioxygenases. Using JMJD2A and JMJD2C as examples, we show that the JMJD2 family of histone demethylases, which are products of putative oncogenes as well as Fe(II)- and αKG-dependent dioxygenases, are highly sensitive to inhibition by Ni(II) ions. In this work, X-ray absorption spectroscopy (XAS) has been used to investigate the Fe(II) active site of truncated JMJD2A and JMJD2C (1-350 amino acids) in the presence and absence of αKG and/or substrate to obtain mechanistic details of the early steps in catalysis that precede O2 binding in histone demethylation by the JMJD2 family of histone demethylases. Zinc K-edge XAS has been performed on the resting JMJD2A (with iron in the active site) to confirm the presence of the expected structural zinc site. XAS of the Ni(II)-substituted enzymes has also been performed to investigate the inhibition of these enzymes by Ni(II) ions. Our XAS results indicate that the five-coordinate Fe(II) center in the resting enzyme is retained in the binary and ternary complexes. In contrast, the Ni(II) center is six-coordinate in the resting enzyme and binary and ternary complexes. XAS results indicate that both Fe(II) and Ni(II) bind αKG in the binary and ternary complexes. The electron density buildup that is observed at the Fe(II) center in the presence of αKG and substrate is not observed at the Ni(II) center. Thus, both electronic and steric factors are responsible for Ni-induced inhibition of the JMJD2 family of histone demethylases. Ni-induced inhibition of these enzymes may explain the alteration of the epigenetic mechanism of gene expression that is responsible for Ni-induced carcinogenesis.
Authors: Yu-ichi Tsukada; Jia Fang; Hediye Erdjument-Bromage; Maria E Warren; Christoph H Borchers; Paul Tempst; Yi Zhang Journal: Nature Date: 2005-12-18 Impact factor: 49.962
Authors: Jonathan M Elkins; Matthew J Ryle; Ian J Clifton; Julie C Dunning Hotopp; John S Lloyd; Nicolai I Burzlaff; Jack E Baldwin; Robert P Hausinger; Peter L Roach Journal: Biochemistry Date: 2002-04-23 Impact factor: 3.162
Authors: Laurens Kruidenier; Chun-wa Chung; Zhongjun Cheng; John Liddle; KaHing Che; Gerard Joberty; Marcus Bantscheff; Chas Bountra; Angela Bridges; Hawa Diallo; Dirk Eberhard; Sue Hutchinson; Emma Jones; Roy Katso; Melanie Leveridge; Palwinder K Mander; Julie Mosley; Cesar Ramirez-Molina; Paul Rowland; Christopher J Schofield; Robert J Sheppard; Julia E Smith; Catherine Swales; Robert Tanner; Pamela Thomas; Anthony Tumber; Gerard Drewes; Udo Oppermann; Dinshaw J Patel; Kevin Lee; David M Wilson Journal: Nature Date: 2012-08-16 Impact factor: 49.962