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The APC/C inhibitor, Emi1, is essential for prevention of re‐replication
Author(s) -
Dutta Anindya,
Machida Yuichi J
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a657-c
Subject(s) - dna replication factor cdt1 , dna re replication , microbiology and biotechnology , biology , cell cycle , ubiquitin ligase , cancer research , genetics , control of chromosome duplication , ubiquitin , cell , gene
Re‐replication of segments of the genome in the same cell cycle has the potential to initiate the genetic instability characteristic of cancers. Indeed, such re‐replication leads to the activation of checkpoint pathways that utilize several genes mutated in cancers, such as BRCA1, p53 and Fanconi anemia. Two redundant pathways are independently capable of inhibiting re‐replication: Geminin, an inhibitor of the replication initiation factor, Cdt1, and cyclin dependent kinases. Emi1 (Early mitotic inhibitor) inhibits the E3 ubiquitin ligase activity of APC/C during S and G2 phases and is believed to be required for proper mitotic entry. Here we report that Emi1 plays an essential function in cell proliferation by preventing rereplication. Rereplication seen after Emi1 depletion is due to premature activation of APC/C that results in destabilization of both geminin and cyclin A. Thus, Emi1 is an Achilles heel whose inactivation disables both the redundant pathways that prevent re‐replication. Endoreduplication of choriocarcinoma cells is a well‐studied model of the endoredupliction of trophoblasts seen during early embryonic development. Consistent with a role in rereplication block, Emi1 is down‐regulated during endoreduplication in these cells. These data suggest that Emi1 plays a critical role in blocking rereplication, revealing a previously unrecognized function of this inhibitor of APC/C.