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Cited by 222Microtubule and mitosis dynamicsDNA Repair MechanismsUbiquitin and proteasome pathways

Regulation of Human Separase by Securin Binding and Autocleavage

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Waizenegger, Irene C., Giménez-Abián, Juan F., Wernic, Dominik, Peters, Jan-Michael·2002·Current Biology
DOI 10.1016/s0960-9822(02)01073-4
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Abstract

Background Sister chromatid separation is initiated by separase, a protease that cleaves cohesin and thereby dissolves sister chromatid cohesion. Separase is activated by the degradation of its inhibitor securin and by the removal of inhibitory phosphates. In human cells, separase activation also coincides with the cleavage of separase, but it is not known if this reaction activates separase, which protease cleaves separase, and how separase cleavage is regulated. Results Inhibition of separase expression in human cells by RNA interference causes the formation of polyploid cells with large lobed nuclei. In mitosis, many of these cells contain abnormal chromosome plates with unseparated sister chromatids. Inhibitor binding experiments in vitro reveal that securin prevents the access of substrate analogs to the active site of separase. Upon securin degradation, the active site of full-length separase becomes accessible, allowing rapid autocatalytic cleavage of separase at one of three sites. The resulting N- and C-terminal fragments remain associated and can be reinhibited by securin. A noncleavable separase mutant retains its ability to cleave cohesin in vitro. Conclusions Our results suggest that separase is required for sister chromatid separation during mitosis in human cells. Our data further indicate that securin inhibits separase by blocking the access of substrates to the active site of separase. Securin proteolysis allows autocatalytic processing of separase into a cleaved form, but separase cleavage is not essential for separase activation.

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  • ESPL1 and PTTG1 regulate the degradation of the APC/C complex during cell cycle arrest.

    “At last, the TPP measurements also reflect complex formation as indicated exemplarily by the interaction of ESPL1 and PTTG1 which regulate the degradation of the APC/C complex during cell cycle arrest (Waizenegger et al, 2002).”

    From Network integration of thermal proteome profiling with multi-omics data decodes PARP inhibition (2024) · cites this paper as Waizenegger et al, 2002

  • Inclusion of TPP allows retrieval of detailed mechanistic insight into well-known consequences of PARP inhibition, such as DNA damage signaling via the ATM-ATR-CHEK2 axis or cell cycle arrest via modulation of cyclin degradation or the formation of the ESPL1-PTTG1 complex.

    “In particular, the inclusion of TPP allows us to retrieve detailed mechanistic insight into well-known consequences of PARP inhibition, such as DNA damage signaling via the ATM-ATR-CHEK2 axis or cell cycle arrest via modulation of cyclin degradation or the formation of the ESPL1-PTTG1 complex (Matthews et al, 2022; Waizenegger et al, 2002).”

    From Network integration of thermal proteome profiling with multi-omics data decodes PARP inhibition (2024) · cites this paper as Waizenegger et al, 2002

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Authors
Waizenegger, I. C., Giménez-Abián, J. F., Wernic, D., & Peters, J.-M.
Affiliations
  • Research Institute of Molecular Pathology (AT)
  • Consejo Superior de Investigaciones Científicas (ES)
  • Boehringer Ingelheim (Canada) (CA)
Corresponding author
Peters, Jan-Michael
ORCID
Venue
Current Biology
Publisher
Elsevier BV
Published
2002-08
Volume
12
Issue
16
Pages
1368-1378
ISSN
0960-9822 (ISSN-L)
DOI
10.1016/s0960-9822(02)01073-4
OpenAlex
W1967853904
Cited by
222
References
40
Citations by year
2026: 7 · 2025: 11 · 2024: 7 · 2023: 8 · 2022: 9 · 2021: 5 · 2020: 8 · 2019: 10 · 2018: 7 · 2017: 15 · 2016: 10 · 2015: 8 · 2014: 6 · 2013: 7 · 2012: 9
FWCI
3.89
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Biology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
separase, securin, sister chromatid separation, cohesin cleavage, sister chromatid cohesion, autocatalytic cleavage, protease activation, mitosis, polyploidy, active site inhibition, RNA interference
MeSH terms
Amino Acid Sequence, Animals, Cell Nucleus, Chromosomal Proteins, Non-Histone, Chromosomes, Enzyme Activation, Enzyme Inhibitors, Fungal Proteins, HeLa Cells, Humans, Mitosis, Models, Biological, Neoplasm Proteins, Nuclear Proteins, Endopeptidases, Peptides, Phosphoproteins, Polyploidy, Protein Binding, Molecular Structure, Trans-Activators, Sequence Alignment, Cell Cycle Proteins, Saccharomyces cerevisiae Proteins, RNA Interference, Separase, Securin

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