Abstract
Timely sister chromatid separation, promoted by separase, is essential for faithful chromosome segregation. Separase is a member of the CD clan of cysteine proteases, which also includes the pro-apoptotic enzymes known as caspases. We report a role for the C. elegans separase SEP-1, primarily known for its essential activity in cell division and cortical granule exocytosis, in developmentally programmed cell death when the predominant pro-apoptotic caspase CED-3 is compromised. Loss of SEP-1 results in extra surviving cells in a weak ced-3(-) mutant, and suppresses the embryonic lethality of a mutant defective for the apoptotic suppressor ced-9/Bcl-2 implicating SEP-1 in execution of apoptosis. We also report apparent non-apoptotic roles for CED-3 in promoting germ cell proliferation, meiotic chromosome disjunction, egg shell formation, and the normal rate of embryonic development. Moreover, loss of the soma-specific (CSP-3) and germline-specific (CSP-2) caspase inhibitors result in CED-3-dependent suppression of embryonic lethality and meiotic chromosome non-disjunction respectively, when separase function is compromised. Thus, while caspases and separases have evolved different substrate specificities associated with their specialized functions in apoptosis and cell division respectively, they appear to have retained the residual ability to participate in both processes, supporting the view that co-option of components in cell division may have led to the innovation of programmed cell suicide early in metazoan evolution.
Highlights
Accurate segregation of chromosomes is essential for faithful transmission of the genome during somatic and germline mitotic proliferation and meiotic divisions associated with gametogenesis
We sought to investigate whether their potential functional overlap might be more than superficial by assessing whether SEP-1 separase is discernibly required for normal programmed cell death (PCD)
Loss of SEP-1 results in early embryonic lethality prior to onset of the developmental PCD as a result of osmotic sensitivity stemming from defects in eggshell formation as well as failure of cytokinesis and proper chromosome segregation[4,8,10,45] To assess later roles of SEP-1, we took advantage of the temperature-sensitive sep-1(e2046) mutation, a missense allele (C450Y) that primarily affects vesicle trafficking and cortical granule exocytosis and that has minimal effect on chromosome segregation8. sep-1(e2046) animals show fully penetrant embryonic lethality at 22 °C, but are viable at 15 °C
Summary
Accurate segregation of chromosomes is essential for faithful transmission of the genome during somatic and germline mitotic proliferation and meiotic divisions associated with gametogenesis. Aneuploidy resulting from defective chromosome segregation can lead to a wide variety of genetic syndromes or embryonic lethality and is associated with most malignant cells types, in some case conferring a growth advantage during cancer progression[1]. The proteases within this clan share conserved tertiary structures, arrangement of catalytic residues, and conserved motifs surrounding the catalytic residues, and apparently arose from a single evolutionary origin[13] (Fig. 1A) The CD clan includes six distinct cysteine proteases, each that carries out unique cellular functions These include the caspases, which are critical executors of apoptosis, or programmed cell death (PCD). We present evidence that two CD clan proteases in C. elegans, the SEP-1 separase and the CED-3 caspase, perform shared roles in cell division and PCD. Our results reveal unexpected promiscuity of clan CD cysteine proteases in the processes of cell division and PCD and raise the possibility that the machinery for PCD may have arisen from components originally required for cell division
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