Disease relevance of ESPL1

• We show that Separase is significantly overexpressed in osteosarcoma, breast, and prostate tumor specimens [1].

High impact information on ESPL1

• Cleavage of cohesin's kleisin subunit by the separase protease then triggers the movement of sister chromatids into opposite halves of the cell during anaphase [2].
• In vertebrate cells, this process is mediated in part by the protease separase, which destroys a small amount of cohesin, but most cohesin is removed from chromosomes without proteolysis [3].
• Separase is inhibited by securin, which is degraded at the metaphase-anaphase transition [4].
• Separation of sister chromatids in anaphase is mediated by separase, an endopeptidase that cleaves the chromosomal cohesin SCC1 [4].
• Mutation of a single phosphorylation site on separase relieves the inhibition and rescues chromatid separation in extracts with high CDC2 activity [4].

Biological context of ESPL1

• Interestingly, RAD21 is cleaved by a caspase-like Esp1/separase at the onset of anaphase to trigger sister chromatid separation [5].
• Inhibitor binding experiments in vitro reveal that securin prevents the access of substrate analogs to the active site of separase [6].
• Essential CDK1-inhibitory role for separase during meiosis I in vertebrate oocytes [7].
• For most of the cell cycle, separase activity is kept in check by its association with the inhibitory chaperone securin [8].
• Also known as a human form of securin, PTTG is an anaphase inhibitor that prevents premature chromosome separation through inhibition of separase activity; hence, its degradation is required to start anaphase [9].

Anatomical context of ESPL1

• Here we show that centriole disengagement requires the protease separase at anaphase, and that this disengagement licences centriole duplication in the next cell cycle [10].

Associations of ESPL1 with chemical compounds

• Separase is a cysteine protease conserved in all eukaryotes and functions to remove sister chromatid cohesion in anaphase by cleaving the SCC1 subunit of the cohesin complex [11].

Physical interactions of ESPL1

• We show that separase is kept inactive under these conditions by a mechanism independent of binding to securin [4].
• Importantly, proper meiotic maturation is rescued by chemical inhibition of Cdk1 or expression of Cdk1-binding separase fragments lacking cohesin-cleaving activity [7].

Regulatory relationships of ESPL1

• Separase is activated by the degradation of its inhibitor securin and by the removal of inhibitory phosphates [6].

Other interactions of ESPL1

• Regulation of human separase by securin binding and autocleavage [6].
• Securin, a chaperone and inhibitor of separase, is ubiquitinated by APC/cyclosome, and degraded by 26S proteasome in anaphase [12].
• Destruction of mitotic cyclin and securin leads to mitotic exit and separase activation, respectively [13].
• Cyclin-B1-mediated inhibition of excess separase is required for timely chromosome disjunction [14].
• Centriole disengagement at anaphase is independent of mitotic exit and Cdk2/cyclin E activity, but requires the anaphase-promoting complex and separase [10].
• PP2A associates with separase through the B' (B56) regulatory subunit and does so independently of securin and cyclin B1 binding [15].

Analytical, diagnostic and therapeutic context of ESPL1

• Blocking separase-Cdk1 complex formation by microinjection of anti-separase antibodies prevents polar-body extrusion in vertebrate oocytes [7].
• The processed forms of human separase were isolated and the identity of the cleavage sites was determined by N-terminal sequencing and site-directed mutagenesis [16].
• First, Western blot analysis demonstrated that the levels of two proteins involved in regulating sister chromatid separation and the spindle checkpoint, Mad2 and separase (ESPL1) were increased in null compared with WT cells [17].
• Based on labeling data and sequence analysis, we propose a model for the structure of separase, consisting of 26 ARM repeats, an unstructured region of 280 residues and two caspase-like domains, with securin binding to the ARM repeats [18].

References