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Título
Characterization of the regulation of APC/CFZR-1 in the germline of Caenorhabditis elegans
Autor(es)
Director(es)
Materia
Tesis y disertaciones académicas
Universidad de Salamanca (España)
Tesis Doctoral
Academic dissertations
Ciclo celular
Meiosis
Proteínas
Clasificación UNESCO
2302.21 Biología Molecular
Fecha de publicación
2022
Resumen
[EN] Cell cycle regulation in dividing and differentiating cells is usually studied
in vitro or in unicellular organism models. However, the C. elegans germline
represents an excellent in vivo model for studying stem cell dynamics and
differentiation. The germline is composed of a pool of stem cells arranged
spatiotemporally, supported by a niche cell called Distal Tip Cell (DTC). As the
stem cells leave the vicinity of the niche, they enter meiosis. This unique physical
organization enables its study by microscopy, which is enhanced by the easiness
of genetic manipulations. The maintenance of the germline features requires the
essential MES-3 and MES-4 chromatin regulators, which previous research in
our group showed to be downregulated by the conserved E3 ubiquitin ligase
APC/CFZR-1
. This cell cycle regulatory complex marks these proteins for
degradation during the transition to meiosis. In this work, we showed that
APC/CFZR-1 is tightly downregulated and upregulated at several different levels to
allow the timely down-regulation of MES-3 and MES-4 proteins. It was intriguing
how the niche could coordinate the signaling to inactivate APC/CFZR-1
in the
mitotic zone. However, as cells differentiate into meiosis, the negative regulation
was timely lifted, and the chromatin regulators were degraded.
In the mitotic zone, the Notch Pathway, through FBF RNA-binding
proteins, represses fzr-1 translation. Indirectly, FBF proteins also activate the
translation of CYE-1 cyclin, resulting in high CDK levels that inhibit APC/CFZR-1
activity. In contrast, upon the cells differentiate to meiosis, APC/CFZR-1 activity is
upregulated through two main pathways: polyA polymerase GLD-2 and another
E3 ubiquitin ligase complex, SCFPROM-1. SCFPROM-1 acts by initiating the
degradation of CYE-1, while GLD-2 promotes new fzr-1 translation and acts
upstream of CKI-2, a conserved CDK inhibitor. We discovered that after
upregulation, APC/CFZR-1 could also recognize and mark for degradation CYE-1,
acting as a backup of SCFPROM-1
. It also recognizes CYA-1, a cyclin highly
expressed at the end of the mitotic zone, and finally, can catalyze the degradation
of its own coactivator, FZR-1.
URI
DOI
10.14201/gredos.152719
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