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Title: Identification of novel APC/C regulators in fission yeast
Author: Ors, Aslihan
ISNI:       0000 0004 2683 1064
Awarding Body: Institute of Cancer Research (University Of London)
Current Institution: Institute of Cancer Research
Date of Award: 2009
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Sequential degradation of cell cycle proteins is a major regulatory mechanism for proper cell proliferation. Turnover of these proteins is performed by the ubiquitin/proteasome pathway, which poly-ubiquitylates and subsequently degrades the target proteins. The anaphase-promoting complex/cyclosome (APC/C) is a multi subunit E3 ubiquitin ligase that provides substrate specificity and regulation of the ubiquitin pathway. Two of the most important substrates are Cut2/securin and Cdc13/cyclin B, enabling chromosome segregation and exit from mitosis, respectively. Since APC/C function is very important for the cell cycle progression, its activity is strictly regulated. The aim of this study is to understand the regulation of APC/C and how its subunits contribute to this regulation. For this purpose, we have focused on the two least understood subunits: Apc1/Cut4 and Apc5. Conditionally lethal temperature sensitive mutants of these two subunits were created in fission yeast and the used for suppressor screening. We identified atf1+ as a multicopy suppressor of apc5-1, a mutation causing mitotic arrest. Fission yeast Atf1, which is homologous to human ATF2/CRE-BP1, is a bZIP domain mutant of Atf1, which has lost its transcription activation function, was still able to suppress the ts phenotype of apc5-1. The atf1+-dependent rescue was specific to the apc5-1 allele, rather than rescuing other APC/C subunit mutants and deletion of atf1+ increased the mitotic defects of the mutant. Interestingly, Atf1 physically binds to the APC/C in vivo. Furthermore, in vitro studies proved that Atf1 stimulates ubiquitylation activity of the APC/C. Finally; this interaction was shown to contribute to conjugation/mating efficiency of S. pombe cells upon nitrogen starvation and G1 arrest. Altogether, these results reveal a novel role for Atf1 in regulating the APC/C ubiquitin ligase, besides its transcription factor activity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available