Arsenic-induced sumoylation of Mus81 is involved in regulating genomic stability.
Chronic environmental exposure to metal toxicants such as chromium and arsenic is closely related to the development of several types of common cancers. Genetic and epigenetic studies in the past decade reveal that post-translational modifications of histones play a role in metal carcinogenesis. However, exact molecular mechanisms of metal carcinogenesis remain to be elucidated. In this study we found that As2O3, an environmental metal toxicant, upregulated overall modifications of many cellular proteins by SUMO2/3. Sumoylated proteins from arsenic-treated cells constitutively expressing His6-SUMO2 were pulled down by Ni-IDA resin under denaturing conditions. Mass spectrometric analysis revealed over 100 proteins that were potentially modified by sumoylation. Mus81, a DNA endonuclease involved in homologous recombination repair, was among the identified proteins whose sumoylation was increased after treatment with As2O3.We further showed that K10 and K524 were 2 lysine residues essential for Mus81 sumoylation. Moreover, we demonstrated that Mus81 sumoylation is important for normal mitotic chromosome congression and that cells expressing SUMO-resistant Mus81 mutants displayed compromised DNA damage responses after exposure to metal toxins such as Cr(VI) and arsenic.
a Department of Environmental Medicine , New York University Langone Medical Center , Tuxedo , NY , USA.
Liyan
L
Hu
b University of Pennsylvania , Philadelphia , PA , USA.
Feikun
F
Yang
c Division of Molecular Medicine, Department of Medicine , David Geffen School of Medicine, University of California Los Angeles , Torrance , CA , USA.
Lou
L
Lu
a Department of Environmental Medicine , New York University Langone Medical Center , Tuxedo , NY , USA.
Wei
W
Dai
D001151:Arsenic / Q000633:toxicity*; D045744:Cell Line, Tumor; D002877:Chromosomes, Human / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004720:Endonucleases / Q000378:metabolism*; D042822:Genomic Instability / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D018832:Molecular Chaperones / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D058207:Sumoylation / Q000187:drug effects*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D004268:DNA-Binding Proteins; D018832:Molecular Chaperones; C484745:PIAS3 protein, human; D050828:Protein Inhibitors of Activated STAT; D044767:Ubiquitin-Protein Ligases; D004720:Endonucleases; C498772:MUS81 protein, human; D008239:Lysine; D001151:Arsenic
DNA damage response; Mus81; arsenic; chromium; sumoylation