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APC/C substrates: how are they disengaged from their non-degraded binding partners?

Project description

Insight into the molecular mechanism of cell division

During mitosis, sister chromatids of each chromosome are equally divided over two newly formed daughter cells. To safeguard genomic stability and ensure error-free division, the APC/C protein complex promotes the progression to anaphase by targeting cell cycle regulators for degradation. The scope of the EU-funded UbiBranch project is to clarify the underlying molecular mechanism by which APC/C functions. Using a multi-disciplinary approach that combines molecular biology, proteomics and in vivo cell biology, scientists will address the control of APC/C on its different substrates. The work aims to unveil novel targets with potential therapeutic value.

Objective

The anaphase promoting complex/ cyclosome (APC/C) is an E3 ubiquitin ligase that controls the cell division cycle by targeting main cell cycle regulators for proteasomal degradation, thereby ensuring error-free cell division and safeguarding genome stability. Its foremost activity is during cell division, or mitosis, when two sets of sister chromatids are equally divided over two newly formed daughter cells.
Intriguingly, APC/C substrates that are degraded at the metaphase-to-anaphase transition have binding partners, which are not degraded. It remains a mystery how the APC/C controls degradation of the substrates and leaves the binding partners undisturbed. My objective is to clarify the molecular mechanism of substrate-binding partner disengagement, and determine the impact of disengagement on substrate degradation, to ensure controlled sister chromatid separation and genome integrity. First, I propose to identify the precise timing of disengagement during the process of ubiquitination, at the molecular level: this will give fundamental insight into disengagement control (Objective 1). Next, I will study ubiquitination at the proteomics level, by unraveling how Lysine-choice, and ubiquitin chain topology affect disengagement (Objective 2). Finally, I will combine conventional molecular biology methods with advanced microscopy techniques to investigate the importance of controlled substrate-binding partner disengagement for substrate degradation and genome stability (Objective 3).
I will employ a multi-disciplinary approach, combining molecular biology, proteomics, and in vivo cell biology approaches to resolve this fundamental biological question. The identified mechanism may provide insights into ternary complex formation of the APC/C and its substrates, which will enable translation to develop targeted-protein-degradation drugs.

Coordinator

ACADEMISCH ZIEKENHUIS LEIDEN
Net EU contribution
€ 187 572,48
Address
ALBINUSDREEF 2
2333 ZA Leiden
Netherlands

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Region
West-Nederland Zuid-Holland Agglomeratie Leiden en Bollenstreek
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 187 572,48