Securin Is Not Required for Chromosomal Stability in Human Cells

Pfleghaar, Katrin; Heubes, Simone; Cox, Jürgen; Stemmann, Olaf; Speicher, Michael R.

doi:10.1371/journal.pbio.0030416

Cited by 53 publications

(52 citation statements)

References 26 publications

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“…In this context, it is reasonable to propose that securin-induced tumor formation might be the result of aneuploidy caused by defects in sister chromatid separation. In fact, both PTTG1 overexpression and PTTG1 depletion (at least transiently) are involved in the induction of aneuploidy (Pfleghaar et al, 2005;Yu et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

UV-induced degradation of securin is mediated by SKP1-CUL1-βTrCP E3 ubiquitin ligase

Limón-Mortés

Mora-Santos

Espina

et al. 2008

Journal of Cell Science

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Securin is a chaperone protein with bifunctional properties. It binds to separase to inhibit premature sister chromatid separation until the onset of anaphase, and it also takes part in cell-cycle arrest after UV irradiation. At metaphase-to-anaphase transition, securin is targeted for proteasomal destruction by the anaphase-promoting complex or cyclosome (APC/C), allowing activation of separase. However, although securin is reported to undergo proteasome-dependent degradation after UV irradiation, the ubiquitin ligase responsible for securin ubiquitylation has not been well characterized. In this study, we show that UV radiation induced a marked reduction of securin in both the nucleus and cytoplasm. Moreover, we show that GSK-3β inhibitors prevent securin degradation, and that CUL1 and βTrCP are involved in this depletion. We also confirmed that SKP1-CUL1-βTrCP (SCFβTrCP) ubiquitylates securin in vivo, and identified a conserved and unconventional βTrCP recognition motif (DDAYPE) in the securin primary amino acid sequence of humans, nonhuman primates and rodents. Furthermore, downregulation of βTrCP caused an accumulation of securin in non-irradiated cells. We conclude that SCFβTrCP is the E3 ubiquitin ligase responsible for securin degradation after UV irradiation, and that it is involved in securin turnover in nonstressed cells.

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Section: Discussionmentioning

confidence: 99%

UV-induced degradation of securin is mediated by SKP1-CUL1-βTrCP E3 ubiquitin ligase

Limón-Mortés

Mora-Santos

Espina

et al. 2008

Journal of Cell Science

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“…Despite securin's conserved role as an inhibitor of separase, it is not essential for maintaining cohesion in mammals. In particular, Securin -/-mice are viable and fertile (Mei et al, 2001;Wang et al, 2001) and human HCT116 cells lacking securin execute mitosis normally (Pfleghaar et al, 2005). Furthermore, in response to spindle toxins, cells that lack securin arrest with cohesed chromosomes (Jallepalli et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Cyclin-B1-mediated inhibition of excess separase is required for timely chromosome disjunction

Holland

Taylor

2006

Journal of Cell Science

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Separase, the cysteine protease that cleaves cohesin and thereby triggers chromosome disjunction, is inhibited by both securin- and phosphorylation-dependent cyclin B1 binding. Using a novel phosphorylation-specific antibody, we show that mitotic-specific phosphorylation of human separase on S1126 is required to establish, but not maintain, cyclin B1 binding. Cells expressing a non-phosphorylatable S1126A mutant maintain cohesion early in mitosis, aligning their chromosomes. Cohesion is then synchronously lost 5 minutes ahead of schedule, without degrading securin or cyclin B1. This premature chromatid disjunction requires the catalytic activity of separase, indicating that it is dependent on cohesin cleavage. Single chromatids then attempt to realign but the lack of tension results in unstable kinetochore-microtubule interactions and Aurora-B-dependent spindle checkpoint activation. Separase mutants that cannot bind cyclin B1 but are phosphorylated on S1126 phenocopy separase S1126A, indicating that cyclin B1 binding, rather than phosphorylation, is the key inhibitory event. Significantly, by overexpressing separase S1126A, we have simultaneously overridden the two known inhibitory mechanisms. First, by elevating separase levels above securin, securin-mediated inhibition is alleviated. Second, by preventing phosphorylation, cyclin-B1-mediated inhibition is also alleviated. Surprisingly, however, cohesion is maintained during the early stages of mitosis, indicating the existence of another mechanism that either inhibits separase or protects its substrate during early mitosis.

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“…10 Pfleghaar et al have recently shed light on this contradiction by showing that transient chromosomal instability in the human securin -/-cell line soon gave way to chromosomal stability. 11 Within a few passages securin -/-cells exhibited a stable karyotype indistinguishable from the parental HCT116 cells. It will be important to clarify whether the transient nature of chromosome losses is due to upregulation of mechanisms that compensate for the loss of securin or simply a result of the insults that incurred by the deletion process.…”

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confidence: 98%