Deficiency of the dual ubiquitin/SUMO ligase Topors results in genetic instability and an increased rate of malignancy in mice

Henderson Marshall, Mantu Bhaumik, Hana Aviv, Dirk Moore, Ming Yao, Jayeeta Dutta, Hussein Rahim, Murugesan Gounder, Shridar Ganesan, Ahamed Saleem, Eric Rubin

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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 HP1α 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.Conclusion: 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.

Original languageEnglish (US)
Article number31
JournalBMC Molecular Biology
Volume11
DOIs
StatePublished - Apr 29 2010

All Science Journal Classification (ASJC) codes

  • Molecular Biology

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