Separase: Function Beyond Cohesion Cleavage and an Emerging Oncogene

Abstract

Proper and timely segregation of genetic endowment is necessary for survival and perpetuation of every species. Mis-segregation of chromosomes and resulting aneuploidy leads to genetic instability, which can jeopardize the survival of an individual or population as a whole. Abnormality with segregation of genetic contents has been associated with several medical consequences including cancer, sterility, mental retardation, spontaneous abortion, miscarriages, and other birth related defects. Separase, by irreversible cleavage of cohesin complex subunit, paves the way for metaphase/anaphase transition during the cell cycle. Both over or reduced expression and altered level of separase have been associated with several medical consequences including cancer, as a result separase now emerges as an important oncogene and potential molecular target for medical intervenes. Recently, separase is also found to be essential in separation and duplication of centrioles. Here, I review the role of separase in mitosis, meiosis, non-canonical roles of separase, separase regulation, as a regulator of centriole disengagement, nonproteolytic roles, diverse substrates, structural insights, and association of separase with cancer. At the ends, I proposed a model which showed that separase is active throughout the cell cycle and there is a mere increase in separase activity during metaphase contrary to the common believes that separase is inactive throughout cell cycle except for metaphase. J. Cell. Biochem. 118: 1283-1299, 2017. © 2016 Wiley Periodicals, Inc.

Conservation of the separase regulatory domain

“…Subsequently, separase cleaves a number of other substrates to regulate several anaphase events [ 9 – 13 ]. Separase is functionally conserved in diverse organisms, including vertebrates, nematodes, fungi, and plants [ 14 ]. Conservation was reported only in the sequence [ 15 – 17 ] and structure of the C-terminal protease domain [ 18 – 20 ].…”

Identification and Analysis of Genes Associated with Epithelial Ovarian Cancer by Integrated Bioinformatics Methods

“…ESPL1, also known as extra spindle poles-like 1 protein or separin, plays a central role in chromosome segregation by cleaving the cohesin complex at the onset of anaphase [27], and altered ESPL1 activity is correlated with aneuploidy and cancer [28]. At present, the results on the roles of ESPL1 in cancers are con icting.…”

Expression and prognostic value of cell-cycle-associated genes in gastric adenocarcinoma

“…ESPL1 , a protease (Separase) encoded gene, was reported overexpressing in mammary adenocarcinomas and related to tumor initiation and progression, but not mentioned in GAC [ 20 ]. According to cleavage of cohesin complex subunit, ESPL1 might promote metaphase/anaphase transition during the cell cycle in GAC [ 21 ]. MCM5 , minichromosome maintenance complex component 5, which encoded protein is involved in the initiation of DNA replication and the effect might reduce the accumulation of genetic variation in GAC.…”