Gene/Protein
Disease
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Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
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Enzyme
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Target Concepts:
Gene/Protein
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Query: UMLS:C0162871 (
abdominal aortic aneurysm
)
8,664
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Separase
, a large protease essential for sister chromatid separation, cleaves the cohesin subunit Scc1/Rad21 during anaphase and leads to dissociation of the link between sister chromatids. Securin, a chaperone and inhibitor of
separase
, is ubiquitinated by APC/cyclosome, and degraded by 26S proteasome in anaphase. Cdc48/VCP/p97, an
AAA
ATPase, is involved in a variety of cellular activities, many of which are implicated in the proteasome-mediated degradation. We previously reported that temperature-sensitive (ts) fission yeast Schizosaccharomyces pombe cdc48 mutants were suppressed by multicopy plasmid carrying the cut1(+)/
separase
gene and that the defective mitotic phenotypes of cut1 and cdc48 were similar. We here describe characterizations of Cdc48 mutant protein and the role of Cdc48 in sister chromatid separation. Mutant residue resides in the conserved D1 domain within the central hole of hexamer, while Cdc48 mutant protein possesses the ATPase activity. Consistent with the phenotypic similarity and the rescue of cdc48 mutant by overproduced Cut1/
separase
, the levels of Cut1 and also Cut2 are diminished in cdc48 mutant. We show that the stability of Cut1 during anaphase requires Cdc48. Cells lose viability during the traverse of anaphase in cdc48 mutant cells. Cdc48 may protect Cut1/
separase
and Cut2/securin against the instability during polyubiquitination and degradation in the metaphase-anaphase transition.
...
PMID:Cdc48 is required for the stability of Cut1/separase in mitotic anaphase. 1690 8
Separation of eukaryotic sister chromatids during the cell cycle is timed by the spindle assembly checkpoint (SAC) and ultimately triggered when
separase
cleaves cohesion-mediating cohesin
1-3
. Silencing of the SAC during metaphase activates the ubiquitin ligase APC/C (anaphase-promoting complex, also known as the cyclosome) and results in the proteasomal destruction of the
separase
inhibitor securin
1
. In the absence of securin, mammalian chromosomes still segregate on schedule, but it is unclear how
separase
is regulated under these conditions
4,5
. Here we show that human shugoshin 2 (SGO2), an essential protector of meiotic cohesin with unknown functions in the soma
6,7
, is turned into a
separase
inhibitor upon association with SAC-activated MAD2. SGO2-MAD2 can functionally replace securin and sequesters most
separase
in securin-knockout cells. Acute loss of securin and SGO2, but not of either protein individually, resulted in
separase
deregulation associated with premature cohesin cleavage and cytotoxicity. Similar to securin
8,9
, SGO2 is a competitive inhibitor that uses a pseudo-substrate sequence to block the active site of
separase
. APC/C-dependent ubiquitylation and action of the
AAA
-ATPase TRIP13 in conjunction with the MAD2-specific adaptor p31
comet
liberate
separase
from SGO2-MAD2 in vitro. The latter mechanism facilitates a considerable degree of sister chromatid separation in securin-knockout cells that lack APC/C activity. Thus, our results identify an unexpected function of SGO2 in mitotically dividing cells and a mechanism of
separase
regulation that is independent of securin but still supervised by the SAC.
...
PMID:Securin-independent regulation of separase by checkpoint-induced shugoshin-MAD2. 3232 60
