Elevated levels of the polo kinase Cdc5 overridethe Mec1/ATR checkpoint in budding yeast by acting at different steps of the signaling pathway
Tesi di Dottorato
Data di Pubblicazione:
2009
Citazione:
Elevated levels of the polo kinase Cdc5 overridethe Mec1/ATR checkpoint in budding yeast by acting at different steps of the signaling pathway / R.a. Donnianni ; tutor: A. Pellicioli ; supervisor: P. Plevani ; coordinatori: R. Mantovani. DIPARTIMENTO DI SCIENZE BIOMOLECOLARI E BIOTECNOLOGIE, 2009 Dec 04. 22. ciclo, Anno Accademico 2008/2009.
Abstract:
Checkpoints are surveillance mechanisms that constitute a barrier to oncogenesis by preserving genome integrity. Loss of
checkpoint function is an early event in tumorigenesis. Polo kinases (Plks) are fundamental regulators of cell cycle
progression in all eukaryotes and are frequently overexpressed in tumors. Through their polo box domain, Plks target
multiple substrates previously phosphorylated by CDKs and MAPKs. In response to DNA damage, Plks are temporally
inhibited in order to maintain the checkpoint-dependent cell cycle block while their activity is required to silence the
checkpoint response and resume cell cycle progression. Here, we report that, in budding yeast, overproduction of the Cdc5
polo kinase overrides the checkpoint signaling induced by double strand DNA breaks (DSBs), preventing the
phosphorylation of several Mec1/ATR targets, including Ddc2/ATRIP, the checkpoint mediator Rad9, and the transducer
kinase Rad53/CHK2. We also show that high levels of Cdc5 slow down DSB processing in a Rad9-dependent manner, but do
not prevent the binding of checkpoint factors to a single DSB. Finally, we provide evidence that Sae2, the functional
ortholog of human CtIP, which regulates DSB processing and inhibits checkpoint signaling, is regulated by Cdc5. We
propose that Cdc5 interferes with the checkpoint response to DSBs acting at multiple levels in the signal transduction
pathway and at an early step required to resect DSB ends.
Tipologia IRIS:
13 - Tesi di dottorato discussa entro ottobre 2010
Elenco autori:
R.A. Donnianni
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