Securin Is a Target of the UV Response Pathway in Mammalian Cells

Abstract

All eukaryotic cells possess elaborate mechanisms to protect genome integrity and ensure survival after DNA damage, ceasing proliferation and granting time for DNA repair. Securin is an inhibitory protein that is bound to a protease called Separase to inhibit sister chromatid separation until the onset of anaphase. At the metaphase-to-anaphase transition, Securin is degraded by the anaphase-promoting complex or cyclosome, and Separase contributes to the release of cohesins from the chromosome, allowing for the segregation of sister chromatids to opposite spindle poles. Here we provide evidence that human Securin (hSecurin) has a novel role in cell cycle arrest after exposure to UV light or ionizing radiation. In fact, irradiation downregulated the level of hSecurin protein, accelerating its degradation via the proteasome and reducing hSecurin mRNA translation, but the presence of hSecurin is necessary for cell proliferation arrest following UV treatment. Moreover, an alteration of UV-induced hSecurin downregulation could lead directly to the accumulation of DNA damage and the subsequent development of malignant tumors.

We thank M. Brandeis (Department of Genetics, Silberman Institute of Life Sciences, Jerusalem, Israel), B. Vogelstein (The John Hopkins Oncology Center), J.-M. Peters (Research Institute of Molecular Pathology, Vienna, Austria), and Robert J. Schultz (Drug Synthesis and Chemistry Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute) for their generous contributions of reagents, without which these studies could not have been performed. We also thank F. Ramos-Morales for critical reading of the manuscript.

This work was supported by grants from Ministerio de Ciencia y Tecnología of Spain (SAF2002-04177-C04), DGUI of the Junta de Andalucía, and Fundación ANDEX. F.R. and C.S. were supported by Ramón y Cajal and Instituto de la Salud Carlos III contracts, respectively.