Deficiency of the dual ubiquitin/SUMO ligase Topors results in genetic instability and an increased rate of malignancy in mice.
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.
Marshall
Henderson
H
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.
Bhaumik
Mantu
M
Aviv
Hana
H
Moore
Dirk
D
Yao
Ming
M
Dutta
Jayeeta
J
Rahim
Hussein
H
Gounder
Murugesan
M
Ganesan
Shridar
S
Saleem
Ahamed
A
Rubin
Eric
E
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*
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