Descripción del proyecto
Información sobre el mecanismo molecular de la división celular
Durante la mitosis, las cromátidas hermanas de cada cromosoma se dividen por igual entre dos células hijas recién formadas. Para salvaguardar la estabilidad genómica y garantizar una división sin errores, el complejo proteínico APC/C promueve el paso a la anafase marcando los reguladores del ciclo celular para la degradación. El objetivo del proyecto UbiBranch, financiado con fondos europeos, es aclarar el mecanismo molecular subyacente del funcionamiento del APC/C. Mediante un método multidisciplinario que combina biología molecular, proteómica y biología celular «in vivo», los científicos abordarán el control del APC/C en sus diferentes sustratos. El proyecto pretende desvelar nuevas dianas con valor terapéutico potencial.
Objetivo
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.
Ámbito científico
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Régimen de financiación
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
2333 ZA Leiden
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