ARTEMIS INTERACTS WITH THE CUL4A UBIQUITIN E3 LIGASE COMPLEX AND REGULATES THE CELL CYCLE PROGRESSION
Data(s) |
01/08/2010
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Resumo |
Artemis, a member of the SNM1 gene family, is one of the six known components of the non-homologous end joining pathway. It is a multifunctional phospho-protein that has been shown to be modified by the phosphatidylinositol 3-kinases (PIKs) DNA-PKcs, ATM and ATR in response to a variety of cellular stresses. Artemis has important roles in V(D)J recombination, DNA double strand breaks repair and damage-induced cell-cycle checkpoint regulation. The detailed mechanism by which Artemis mediates its functions in these cellular pathways needs to be further elucidated. My work presented here demonstrates a new function for Artemis in cell cycle regulation as a component of Cullin-based E3 ligase complex. I show that Artemis interacts with Cul4A-DDB1 ligase complex via a direct interaction with the substrate-specific receptor DDB2, and deletion mapping analysis shows that part of the Snm1 domain of Artemis is responsible for this interaction. Additionally, Artemis also interacts with p27, a substrate of Cul4A-DDB1 complex, and both DDB2 and Artemis are required for the degradation of p27 mediated by this complex. Furthermore, I show that the regulation of p27 by Artemis and DDB2 is critical for cell cycle progression in normally proliferating cells and in response to serum withdrawal. Finally, I provide evidence showing that Artemis may be also a part of other Cullin-based E3 ligase complexes, and it has a role in controlling p27 levels in response to different cellular stress, such as UV irradiation. These findings suggest a novel pathway to regulate p27 protein level and define a new function for Artemis as an effector of Cullin-based E3-ligase mediated ubiquitylation, and thus, a cell cycle regulator in proliferating cells. |
Formato |
application/pdf |
Identificador |
http://digitalcommons.library.tmc.edu/utgsbs_dissertations/60 http://digitalcommons.library.tmc.edu/cgi/viewcontent.cgi?article=1084&context=utgsbs_dissertations |
Publicador |
DigitalCommons@The Texas Medical Center |
Fonte |
UT GSBS Dissertations and Theses (Open Access) |
Palavras-Chave | #Artemis #DDB #Cul #p27 #Ubiquitin #Cell Cycle #Cell and Developmental Biology #Molecular Biology |
Tipo |
text |