Human Securin Research Articles

Full and D-Box-Deficient PTTG1 Isoforms: Effects on Cell Proliferation

Human securin (PTTG1) is a protooncogene whose expression is elevated in many types of malignant cells. We previously discovered a minor short isoform of securin lacking exons 3 and 4. The missing exons encode the main recognition site (D-box) of the anaphase-promoting complex (APC/C). We show that these two PTTG1 isoforms have different effects on transcription. Here, we have studied the effects of overexpression and selective knockdown of the short and complete securin isoforms on cell proliferation using the xCELLigence system. Notably, selective knockdown of the short isoform mRNA led to a dramatic decrease in cell growth, while overexpression of both isoforms accelerated cell growth. To search for genes with alternative isoforms similar to securin, we analyzed the GENCODE database and found that 54 of 128 genes with a PTTG1-like set of APC/C recognition sites have known isoforms without the D-box. Overall, the data obtained indicate the existence of a new class of alternative isoforms and reinstates the importance of minor isoforms.

Structural basis of human separase regulation by securin and CDK1-cyclin B1.

In early mitosis, the duplicated chromosomes are held together by the ring-shaped cohesin complex1. Separation of chromosomes during anaphase is triggered by separase-a large cysteine endopeptidase that cleaves the cohesin subunit SCC1 (also known as RAD212-4). Separase is activated by degradation of its inhibitors, securin5 and cyclin B6, but the molecular mechanisms of separase regulation are not clear. Here we used cryogenic electron microscopy to determine the structures of human separase in complex with either securin or CDK1-cyclin B1-CKS1. In both complexes, separase is inhibited by pseudosubstrate motifs that block substrate binding at the catalyticsite and at nearby docking sites. As in Caenorhabditis elegans7 and yeast8, human securin contains its own pseudosubstrate motifs. By contrast, CDK1-cyclin B1 inhibits separase by deploying pseudosubstrate motifs from intrinsically disordered loops in separase itself. One autoinhibitory loop is oriented by CDK1-cyclin B1 to block the catalyticsites of both separase and CDK19,10. Another autoinhibitory loop blocks substrate docking in a cleft adjacent to the separase catalytic site. A third separase loop contains a phosphoserine6 that promotes complex assembly by binding to a conserved phosphate-binding pocket in cyclin B1. Our study reveals the diverse array of mechanisms by which securin and CDK1-cyclin B1 bind and inhibit separase, providing the molecular basis for the robust control of chromosome segregation.

Systematic Identification and Competitive Disruption of Securin-Binding Partners in the Gene Diversity Space of Human Colorectal Cancer.

Human securin is regulatory protein involved in control of the metaphase-anaphase transition and anaphase onset of colorectal cancer. Molecular evidences suggest that the protein is integrated into oncogenic signaling network by binding to SH3-containing proteins through its proline-rich peptides. In this study, we have performed a genome-wide analysis and identification of securin-binding partners in the gene diversity space of human colorectal cancer. The securin-binding potency of SH3-containing proteins found in colorectal cancer was investigated by using bioinformatics modeling and intermolecular assay. With the protocol we were able to predict those high-affinity domain binders of the proline-rich peptides of human securin in a high-throughput manner, and to analyze sequence-specific interaction in the domain-peptide recognition at molecular level. Consequently, a number of putative domain binders with both high affinity and specificity were identified, from which the Src SH3 domain was selected as a case study and tested for its binding activity towards the securin peptides using fluorescence-based analysis. We also designed two peptide mutants that may have potent capability to competitively disrupt securin interaction with its partners. This article is protected by copyright. All rights reserved.

Structure-Based Identification, Characterization, and Disruption of Human Securin-Binding SH3 Domains in Lung Cancer

ABSTRACTThe human securin is an oncogenic transcription factor that has been found to promote migration and invasion of lung cancer and many other tumors. The protein contains a PxxP motif that can be recognized and bound by diverse cellular partners via Src homology (SH3) domain to regulate biological and pathological events. The motif is covered by a decapeptide segment 161LGPPSPVKMP170 (SecPeptide) as the potential binding site of SH3 domains. Here, we attempted to systemically identify the SH3 binding partners of human securin in lung cancer and to characterize the intermolecular interaction between SecPeptide and the identified SH3 domains. A bioinformatics protocol that integrated literature curation, complex structural modeling, and binding affinity analysis was described to perform systematic search against an array of SH3-containing proteins involved in lung cancer signaling pathway and, consequently, three putative domains, namely GRB2, CRK, and RasGAP, were identified that have high potential to recognize and bind SecPeptide. The molecular mechanism and biological implication underlying the intermolecular interaction between these domains and SecPetide were investigated at structural and energetic level. Surface plasmon resonance assay revealed a high or moderate affinity of SecPeptide and its two mutants binding to CRK-SH3 domain with dissociation constants Kd = 79.8, 24.2, and 64.6 µM, respectively.

Prostate cancer cell response to paclitaxel is affected by abnormally expressed securin PTTG1.

PTTG1 protein, the human securin, has a central role in sister chromatid separation during mitosis, and its altered expression has been reported in many tumor types. Paclitaxel is a widely used chemotherapeutic drug, whose mechanism of action is related to its ability to arrest cells in mitosis and the subsequent induction of the intrinsic apoptotic pathway. By using two prostate cancer cell lines with different responses to paclitaxel treatment, we have identified two situations in which PTTG1 influences cell fate differentially. In slippage-prone PC3 cells, both PTTG1 downregulation and overexpression induce an increase in mitotic cells that is associated with diminished apoptosis after paclitaxel treatment. In LNCaP cells, however, PTTG1 downregulation prevents mitotic entry and, subsequently, inhibits mitosis-associated, paclitaxel-induced apoptosis. In contrast, PTTG1 overexpression induces an increase in mitotic cells and apoptosis after paclitaxel treatment. We have also identified a role for Mcl-1 protein in preventing apoptosis during mitosis in PC3 cells, as simultaneous PTTG1 and Mcl-1 silencing enhances mitosis-associated apoptosis after paclitaxel treatment. The finding that a more efficient mitotic arrest alone in PC3 cells is not enough to increase apoptosis was also confirmed with the observation that a selected paclitaxel-resistant PC3 cell line showed an apoptosis-resistant phenotype associated with increased mitosis upon paclitaxel treatment. These findings could contribute to identify putative responsive and nonresponsive cells and help us to approach incomplete responses to paclitaxel in the clinical setting.

PTTG2 silencing results in induction of epithelial-to-mesenchymal transition and apoptosis

Human securin, also known as human pituitary tumor-transforming gene 1 (pttg1), plays a key role in cell-cycle regulation. Two homologous genes, pttg2 and pttg3, have been identified although very little is known about their physiological function. In this study, we aimed at the characterization of these two pttg1 homologs. Real-time PCR analysis using specific probes demonstrated that Pttg2 is expressed at very low levels in various cell lines and tissues whereas Pttg3 was largely undetectable. We focused on the study of Pttg2 and found that, unlike PTTG1, PTTG2 lacks transactivation activity and does not bind to separase, making improbable a role in the control of sister chromatids separation. To further investigate the biological role of pttg2, we used short hairpin RNA inhibition of Pttg2 and found that cells with reduced Pttg2 levels assumed a rounded morphology compatible with a defect in cell adhesion and died by apoptosis in a p53- and p21-dependent manner. Using microarray technology, we generated a gene expression profile of Pttg2-depleted cells versus wild-type cells and found that knockdown of PTTG2 results in concomitant downregulation of E-cadherin and elevated vimentin levels, consistent with EMT induction. The observation of aberrant cellular behaviors in Pttg2-silenced cells reveals functions for pttg2 in cell adhesion and provides insights into a potential role in cell invasion.

Clusterin and FOXL2 Act Concordantly to Regulate Pituitary Gonadotroph Adenoma Growth

Pituitary tumors grow slowly and despite their high prevalence are invariably benign. We therefore studied mechanisms underlying pituitary tumor growth restraint. Pituitary tumor transforming gene (PTTG), the index human securin, a hallmark of pituitary tumors, triggers pituitary cell proliferation and murine pituitary tumor development. We show that human gonadotroph cell pituitary tumors, unlike other secreting tumor types, express high levels of gonadotroph-specific forkhead transcription factor FOXL2, and both PTTG and Forkhead box protein L2 (FOXL2) stimulate gonadotroph clusterin (Clu) expression. Both Clu RNA isoforms are abundantly expressed in these nonhormone-secreting human tumors, and, when cultured, these tumor cells release highly abundant levels of secreted Clu. FOXL2 directly stimulates the Clu gene promoter, and we show that PTTG triggers ataxia telangiectasia mutated kinase/IGF-I/p38MAPK DNA damage/chromosomal instability signaling, which in turn also induces Clu expression. Consequently, Clu restrains pituitary cell proliferation by inducing cyclin dependent kinase inhibitors p16 and p27, whereas Clu deletion down-regulates p16 and p27 in the Clu(-/-) mouse pituitary. FOXL2 binds and suppresses the PTTG promoter, and Clu also suppresses PTTG expression, thus neutralizing protumorigenic PTTG gonadotroph tumor cell properties. In vivo, murine gonadotroph LβT2 tumor cell xenografts overexpressing Clu and FOXL2 both grow slower and elicit smaller tumors. Thus, gonadotroph tumor cell proliferation is determined by the interplay between cell-specific FOXL2 with PTTG and Clu.

The pituitary tumor transforming gene in thyroid cancer.

The pituitary tumor transforming gene (PTTG) is a multifunctional proto-oncogene that is over-expressed in various tumors including thyroid carcinomas, where it is a prognostic indicator of tumor recurrence. PTTG has potent transforming capabilities in vitro and in vivo, and many studies have investigated the potential mechanisms by which PTTG contributes to tumorigenesis. As the human securin, PTTG is involved in critical mechanisms of cell cycle regulation, whereby aberrant expression induces aneuploidy. PTTG may further contribute to tumorigenesis through its role in DNA damage response pathways and via complex interactions with hormones and growth factors. Furthermore, PTTG over-expression negatively impacts upon the efficacy of radioiodine therapy in thyroid cancer, through repression of expression and function of the sodium iodide symporter. Given its various roles at all disease stages, PTTG appears to be an important oncogene in thyroid cancer. This review discusses the current knowledge of PTTG with particular focus on its role in thyroid cancer.

Expression and function of the novel proto-oncogene PBF in thyroid cancer: a new target for augmenting radioiodine uptake

Pituitary tumor-transforming gene (PTTG)-binding factor (PBF; PTTG1IP) was initially identified through its interaction with the human securin, PTTG. Like PTTG, PBF is upregulated in multiple endocrine tumours including thyroid cancer. PBF is believed to induce the translocation of PTTG into the cell nucleus where it can drive tumourigenesis via a number of different mechanisms. However, an independent transforming ability has been demonstrated both in vitro and in vivo, suggesting that PBF is itself a proto-oncogene. Studied in only a limited number of publications to date, PBF is emerging as a protein with a growing repertoire of roles. Recent data suggest that PBF possesses a complex multifunctionality in an increasing number of tumour settings. For example, PBF is upregulated by oestrogen and mediates oestrogen-stimulated cell invasion in breast cancer cells. In addition to a possible role in the induction of thyroid tumourigenesis, PBF overexpression in thyroid cancers inhibits iodide uptake. PBF has been shown to repress sodium iodide symporter (NIS) activity by transcriptional regulation of NIS expression through the human NIS upstream enhancer and further inhibits iodide uptake via a post-translational mechanism of NIS governing subcellular localisation. This review discusses the current data describing PBF expression and function in thyroid cancer and highlights PBF as a novel target for improving radioiodine uptake and thus prognosis in thyroid cancer.

Pituitary tumor-transforming gene and its binding factor in endocrine cancer

The pituitary tumor-transforming gene (PTTG1) encodes a multifunctional protein (PTTG) that is overexpressed in numerous tumours, including pituitary, thyroid, breast and ovarian carcinomas. PTTG induces cellular transformation in vitro and tumourigenesis in vivo, and several mechanisms by which PTTG contributes to tumourigenesis have been investigated. Also known as the human securin, PTTG is involved in cell cycle regulation, controlling the segregation of sister chromatids during mitosis. This review outlines current information regarding PTTG structure, expression, regulation and function in the pathogenesis of neoplasia. Recent progress concerning the use of PTTG as a prognostic marker or therapeutic target will be considered. In addition, the PTTG binding factor (PBF), identified through its interaction with PTTG, has also been established as a proto-oncogene that is upregulated in several cancers. Current knowledge regarding PBF is outlined and its role both independently and alongside PTTG in endocrine and related cancers is discussed.

Overexpression of the Pituitary Tumor Transforming Gene Induces p53-dependent Senescence through Activating DNA Damage Response Pathway in Normal Human Fibroblasts

Pituitary tumor transforming gene (PTTG1, securin) is involved in cell-cycle control through inhibition of sister-chromatid separation. Elevated levels of PTTG1 were found to be associated with many different tumor types that might be involved in late stage tumor progression. However, the role of PTTG1 in early stage of tumorigenesis is unclear. Here we utilized the adenovirus expression system to deliver PTTG1 into normal human fibroblasts to evaluate the role of PTTG1 in tumorigenesis. Expressing PTTG1 in normal human fibroblasts inhibited cell proliferation. Several senescence-associated (SA) phenotypes including increased SA-beta-galactosidase activities, decreased bromodeoxyuridine incorporation, and increased SA-heterochromatin foci formation were also observed in PTTG1-expressing cells, indicating that PTTG1 overexpression induced a senescent phenotype in normal cells. Significantly, the PTTG1-induced senescence is p53-dependent and telomerase-independent, which is distinctively different from that of replicative senescence. The mechanism of PTTG1-induced senescence was also analyzed. Consistent with its role in regulating sister-chromatid separation, overexpression of PTTG1 inhibited the activation of separase. Consequently, the numbers of cells with abnormal nuclei morphologies and chromosome separations were increased, which resulted in activation of the DNA damage response. Thus, we concluded that PTTG1 overexpression in normal human fibroblasts caused chromosome instability, which subsequently induced p53-dependent senescence through activation of DNA-damage response pathway.

Structural and Dynamic Characterization of Intrinsically Disordered Human Securin by NMR Spectroscopy

Understanding the molecular action of securin, the inhibitor of separase in mitosis, is of immense theoretical and biomedical importance. The residue-level structural description of an intrinsically disordered protein of this length (202 amino acids, containing 24 prolines), however, represents a particular challenge. Here we combined (1)H-detected and (13)C-detected protonless NMR experiments to achieve full assignment of securin's backbone amide resonances. Chemical shifts, (15)N relaxation rates (R(1), R(2), (1)H-(15)N NOEs), (1)H exchange rates with the solvent (CLEANEX-PM), and (1)H-(15)N residual dipolar couplings were determined along the entire length of the protein. This analysis showed that securin is not entirely disordered, but segregates into a largely disordered N-terminal half and a C-terminal half with transient segmental order, within which the segment D(150)-F(159) has a significant helical tendency and segments E(113)-S(127) and W(174)-L(178) also show a significant deviation from random-coil behavior. These results, in combination with bioinformatic and biochemical data on the securin/separase interaction, shed light on the inhibitory action of securin on separase.

HDAC and Hsp90 inhibitors down‐regulate PTTG1/securin but do not induce aneuploidy

Human securin regulates correct chromatid separation. However, there are conflicting reports on the aneugenic effects of its gene deletion. Here we show that PTTG1/securin gene expression is dramatically repressed when Hsp90 or histone deacetylases are inhibited. However, these treatments do not increase the proportion of aneuploid cells. This was also confirmed using RNAi (silencing of PTTG1/securin > or =80%). As expected, histone deacetylases arrested cells in both G1 and G2. However, sec(-/-) HCT116 cells showed a greater disposition to arrest cells in G2 than sec(+/+) cells due to insufficient induction of CDKN1A. These results indicate that chromatid separation is controlled through redundant mechanisms and reveal a new aspect of securin in cell cycle regulation.

Precocious activation of APC/C-Cdh1 at pre-anaphase causes genome instability

AbstractFaithful chromosome segregation and thereby accurate gene transmission are crucial for all organisms. Until proper attachment of the mitotic spindle to the kinetochore is established, the ubiquitin ligase (E3) Cdc20-activated APC/C (anaphase promoting complex/cyclosome) is repressed by the spindle assembly checkpoint (SAC) and sister chromatin cohesion is protected. Mutants defective in SAC fail to arrest at metaphase even in the presence of damaged microtubules. Interestingly, a similar phenomenon occurs in yeast cells defective in Bub2, a negative factor of the mitotic exit network (MEN), which is required for telophase onset, although its precise molecular mechanism is unknown. Here, we show that chromosome missegregation occurs frequently in bub2&x2206; cells in the presence of damaged microtubules. The loss of Bub2 caused precocious activation of APC/C-Cdh1/Hct1 at pre-anaphase, leading to securin degradation and then separase-mediated cohesin cleavage. Overexpression of CDH1 and CDC14, encoding Cdc14 phosphatase, at pre-anaphase similarly caused chromosome missegregation. Thus, sequential activation of APC/C-Cdc20 and then APC/C-Cdh1 is critical for precise chromosome segregation and precocious activation of APC/C-Cdh1 at pre-anaphase causes genomic instability. Since degradation of human securin is also mediated by APC/C-Cdc20 and APC/C-Cdh1, this study predicts that precocious activation APC/C-Cdh1 in human cells similarly causes genomic instability, and thereby cell death or tumorigenesis.

Protein Phosphatase 2A Stabilizes Human Securin, Whose Phosphorylated Forms Are Degraded via the SCF Ubiquitin Ligase

Sister chromatid segregation is triggered at the metaphase-to-anaphase transition by the activation of the protease separase. For most of the cell cycle, separase activity is kept in check by its association with the inhibitory chaperone securin. Activation of separase occurs at anaphase onset, when securin is targeted for destruction by the anaphase-promoting complex or cyclosome E3 ubiquitin protein ligase. This results in the release of the cohesins from chromosomes, which in turn allows the segregation of sister chromatids to opposite spindle poles. Here we show that human securin (hSecurin) forms a complex with enzymatically active protein phosphatase 2A (PP2A) and that it is a substrate of the phosphatase, both in vitro and in vivo. Treatment of cells with okadaic acid, a potent inhibitor of PP2A, results in various hyperphosphorylated forms of hSecurin which are extremely unstable, due to the action of the Skp1/Cul1/F-box protein complex ubiquitin ligase. We propose that PP2A regulates hSecurin levels by counteracting its phosphorylation, which promotes its degradation. Misregulation of this process may lead to the formation of tumors, in which overproduction of hSecurin is often observed.

Prognostic Significance of Human Pituitary Tumor-Transforming Gene Immunohistochemical Expression in Differentiated Thyroid Cancer

Human securin pituitary tumor-transforming gene (hPTTG) is overexpressed in a variety of primary neoplasias, including differentiated thyroid cancer (DTC). The objective of this study was to examine the immunohistochemical expression of hPTTG in DTC and its association with known prognostic factors. hPTTG expression was analyzed by immunostaining on paraffin-embedded tissues. Clinical data were used to determine any associations between the expression of hPTTG and prognostic variables of DTC. A median follow-up of 43 months allowed us to analyze the persistence of disease and the response to radioiodine therapy. The study was conducted at a tertiary university hospital. Ninety-five patients undergoing surgical resection for DTC (n = 60) or benign nodular thyroid disease (n = 35) were studied. The main outcome measure was the association between hPTTG expression and prognostic factors in DTC. Among DTC cases, 21 (35%) had low and 39 (65%) had high hPTTG immunostaining. Adjacent nonneoplastic thyroid tissue was largely unstained. Among benign nodular thyroid disease cases, immunostaining was detected focally in eight (22.8%). A significant association was found between hPTTG expression and the presence of nodal (P < 0.01) or distant metastases (P < 0.05). A significant association with TNM was also found, because 83.3% of advanced TNM stages showed elevated hPTTG (P < 0.05). The association between hPTTG overexpression and decreased radioiodine uptake during follow-up was also significant (P < 0.05). The expression levels of hPTTG were confirmed as an independent prognostic factor for persistent disease (relative risk, 3.0; 95% confidence interval, 1.1-8.7; P < 0.05). Immunohistochemical analysis of hPTTG is of potential value in the determination of tumor aggressiveness in DTC.

Overexpression of pituitary tumor transforming gene 1 in HCC is associated with angiogenesis and poor prognosis†

The pituitary tumor transforming gene 1 (PTTG1) protein is cell-cycle regulated and is identified as a human securin that inhibits sister chromatid separation and is involved in transformation and tumorigenesis. PTTG1 has very low or undetectable expression in most normal human tissues, but it is abundantly expressed in malignant cell lines and pituitary tumors. In this study, we investigated human PTTG1 expression in 62 hepatocellular carcinoma (HCC) specimens using quantitative real-time reverse transcription polymerase chain reaction analysis. We found that, compared with corresponding noncancerous liver tissues, PTTG1 was remarkably overexpressed in HCCs (PTTG1/beta-actin; 0.443 +/- 0.073 vs. 0.068 +/- 0.007; P < .0001). Furthermore, we found a significant correlation between PTTG1 expression and serum alpha-fetoprotein level (P < .001). Univariate and multivariate analyses revealed that the PTTG1 messenger RNA (mRNA) expression was an independent prognostic factor for disease-free (odds ratio 2.70; P = .037) and overall (odds ratio 5.35; P = .007) survival. Moreover, we discovered a significant relationship between PTTG1 expression and intratumoral microvessel density. Our data supported an important role for PTTG1-mediated upregulation of fibroblast growth factor (FGF)-2, one of angiogenesis and modulation of tumor progression, in hepatocarcinogenesis. In conclusion, PTTG1 might be critically involved in the development of HCCs through the promotion of angiogenesis. PTTG1 is overexpressed in HCC and our results suggest that PTTG1 mRNA expression has prognostic significance for the survival of postoperative patients with HCC.

Human full‐length Securin is a natively unfolded protein

Human Securin, also called PTTG1 (pituitary tumor transforming gene 1 product), is an estrogen-regulated proto-oncogene with multifunctional properties. We characterized human full-length Securin using a variety of biophysical techniques, such as nuclear magnetic resonance, circular dichroism, and size-exclusion chromatography. Under physiological conditions, Securin is devoid of tertiary and secondary structure except for a small amount of poly-(L-proline) type II helix and its hydrodynamic characteristics suggest it behaves as an extended polypeptide. These results suggest that Securin is unstructured in solution and so belongs to the family of natively unfolded proteins. In addition, to gain structural and quantitative insight, we investigated the binding of Securin to p53. Analytical ultracentrifugation and fluorescence anisotropy studies revealed no evidence of any direct interaction between unmodified recombinant Securin and p53 in vitro.

Expression of pituitary tumor transforming gene (PTTG) and its binding protein in human astrocytes and astrocytoma cells: function and regulation of PTTG in U87 astrocytoma cells.

Human securin, pituitary tumor transforming gene (PTTG), is a protooncogene. Here we report expressions of PTTG and its interacting protein, PTTG-binding factor in human astrocytic cells. PTTG expression was higher in malignant cells than in primary astrocytes, whereas PTTG-binding factor was not. Using a xenotransplantable, glioma cell line (U87), we observed that knocking down PTTG mRNA by RNA silencing inhibited serum-induced proliferation by approximately 50%. Furthermore, in U87 cells PTTG expression was up-regulated by promalignant ligands epithelial growth factor (EGF) and TGFalpha, both at the protein and mRNA levels. PTTG induction by EGF receptor (EGFR) ligands could be blocked by the specific EGFR inhibitor, AG1478. Hepatocyte growth factor (HGF) also induced PTTG but to a lesser extent than EGF. Although EGF stimulates HGF secretion in U87 cells, the effect of EGF on PTTG mRNA expression is independent of HGF as neutralizing antibody against HGF failed to abolish EGF-induced up-regulation of PTTG mRNA. PTTG mRNA was unchanged by incubating U87 cells with the promalignant growth factor TGFbeta, apoptosis inducing TNFalpha and ligands for nuclear receptors, such as retinoic acid and retinoid X receptors and peroxisome proliferator-activated receptor-gamma, known for their growth-inhibitory and apoptosis-inducing effects on gliomas. In addition, 17beta-estradiol and Ca2+, known to activate PTTG expression, did not change PTTG mRNA levels in U87 cells. In summary, we show higher PTTG expression in astrocytoma than normal astrocytes and secondly, PTTG is involved in glioma cell growth. Finally, regulation of its expression has glioma-specific features and is selectively regulated by promalignant cytokines including EGFR ligands and HGF.

Securin is a target of the UV response pathway in mammalian cells.

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.