title: Deficiency of the dual ubiquitin/SUMO ligase Topors results in genetic instability and an increased rate of malignancy in mice.
abstract: BACKGROUND
  Topors is a nuclear protein that co-localizes with promyelocytic leukemia bodies and has both ubiquitin and SUMO E3 ligase activity. Expression studies implicated Topors as a tumor suppressor in various malignancies. To gain insight into the function of Topors, we generated a Topors-deficient mouse strain.
  
  
  RESULTS
  Mice homozygous for a mutant Topors allele exhibited a high rate of perinatal mortality and decreased lifespan. In addition, heterozygotes were found to have an increased incidence of malignancy, involving a variety of tissues. Consistent with this finding, primary embryonic fibroblasts lacking Topors exhibited an increased rate of malignant transformation, associated with aneuploidy and defective chromosomal segregation. While loss of Topors did not alter sensitivity to DNA-damaging or microtubule-targeting agents, cells lacking Topors exhibited altered pericentric heterochromatin, manifested by mislocalization of HP1alpha and an increase in transcription from pericentric major satellite DNA. Topors-deficient cells exhibited a transcriptional profile similar to that of cells treated with histone deacetylase inhibitors, and were resistant to the anti-proliferative effects of the histone deacetylase inhibitor trichostatin A.
  
  
  CONCLUSIONS
  These results indicate a unique role for Topors in the maintenance of genomic stability and pericentric heterochromatin, as well as in cellular sensitivity to histone deacetylase inhibitors.
authors.affiliation: Department of Pharmacology, Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA.
authors.forename: Henderson
authors.initials: H
authors.lastname: Marshall
authors.forename: Mantu
authors.initials: M
authors.lastname: Bhaumik
authors.forename: Hana
authors.initials: H
authors.lastname: Aviv
authors.forename: Dirk
authors.initials: D
authors.lastname: Moore
authors.forename: Ming
authors.initials: M
authors.lastname: Yao
authors.forename: Jayeeta
authors.initials: J
authors.lastname: Dutta
authors.forename: Hussein
authors.initials: H
authors.lastname: Rahim
authors.forename: Murugesan
authors.initials: M
authors.lastname: Gounder
authors.forename: Shridar
authors.initials: S
authors.lastname: Ganesan
authors.forename: Ahamed
authors.initials: A
authors.lastname: Saleem
authors.forename: Eric
authors.initials: E
authors.lastname: Rubin
mesh_terms: D000818:Animals; D000090266:Chromobox Protein Homolog 5; D005347:Fibroblasts; D042822:Genomic Instability; D006579:Heterozygote; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids; D051379:Mice; D009369:Neoplasms / Q000235:genetics*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: C000715594:CBX5 protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D025841:Small Ubiquitin-Related Modifier Proteins; D025521:Tumor Suppressor Proteins; D000090266:Chromobox Protein Homolog 5; C012589:trichostatin A; C550140:Topors protein, mouse; D044767:Ubiquitin-Protein Ligases