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Cell Cycle, Cell Death, and Senescence

Defective in Mitotic Arrest 1/Ring Finger 8 Is a Checkpoint Protein That Antagonizes the Human Mitotic Exit Network

¹ The Wistar Institute, ² Biomedical Graduate Studies, ³ Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and ⁴ Departments of Molecular Biology and Biochemistry, University of Geneva, Geneva, Switzerland

Requests for reprints: Thanos D. Halazonetis, Department of Molecular Biology, University of Geneva, 30 quai Ernest-Ansermet, CH-1211 Geneva 4, Switzerland. Phone: 41-22-379-61-12; Fax: 41-22-379-68-68. E-mail: thanos.halazonetis{at}molbio.unige.ch

A molecular pathway homologous to the S. cerevisiae mitotic exit network (MEN) and S. pombe septation initiation network has recently been described in higher eukaryotes and involves the tumor suppressor kinase LATS1 and its subunit MOB1A. The yeast MEN/septation initiation network pathways are regulated by the ubiquitin ligase defective in mitotic arrest 1 (Dma1p), a checkpoint protein that helps maintain prometaphase arrest when cells are exposed to microtubule poisons. We identified here the RING domain protein ring finger 8 (RNF8) as the human orthologue of the yeast protein Dma1p. Like its yeast counterparts, human DMA1/RNF8 localized at the midbody and its depletion by siRNA compromised mitotic arrest of nocodazole-treated cells in a manner dependent on the MEN. Depletion of MAD2, a spindle checkpoint protein, also compromised mitotic arrest, but in a MEN-independent manner. Thus, two distinct checkpoint pathways maintain mitotic arrest in cells exposed to microtubule poisons. (Mol Cancer Res 2007;5(12):1304–11)