Doctoral thesis (Dissertations and theses)
Role of NF-κB p65 subunit phosphorylation by ATM in DNA damage-regulated gene expression
Sabatel, Hélène
2012
 

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Keywords :
ATM; p65; NF-kappaB
Abstract :
[en] DNA damage, induced by several genotoxic agents, challenge genome integrity. Among the different types of DNA lesions, DNA double-strand breaks (DSB) are the most deleterious. Indeed, if not correctly repaired, they can lead to cell death or carcinogenesis. Upon DSB, cells activate a complex signaling network, the DNA damage response (DDR), to counteract those threats. The DDR coordinates DSB repair, checkpoint activation, apoptosis and transcription factors regulation, including NF-κB.   NF-κB family is composed of 5 proteins (RelA/p65, RelB, c-Rel, p105/p50 and p100/p52) which assemble in dimers to form active NF-κB transcription factor. In resting cells, NF-κB complexes are bound to inhibitor proteins such as IκBα, and maintained inactive in the cytoplasm. Classical NF-κB activation requires activation of IκB kinase (IKK) complex, which phosphorylates IκBα, finally leading to its degradation. NF-κB transcription factor is then free to translocate to the nucleus where it regulates a wide array of target genes. NF-κB is an important regulator of diverse cellular processes, including immune response, inflammation, cell survival, proliferation, differentiation, adhesion and apoptosis. NF-κB activation is associated to several pathogenesis and especially contributes to the growth and malignancy of cancer cells. NF-κB also affects the tumor response to many types of chemotherapy and ionizing radiation. Therefore the understanding of the regulation mechanisms of this transcription factor represent a major concern.   This work was interested in the regulation mechanism of DSB-induced NF-κB via the direct phosphorylation of the NF-κB subunit p65 by ATM kinase, the main mediator protein of the DDR. Indeed, rapidly activated in response to DSB, this kinase phosporylates a huge amount of substrates involved in different cellular functions. It had been previously shown that ATM was required for DSB-induced NF-κB activation by acting at two levels. On the one hand, activated ATM phosphorylates the IKK regulatory subunit NEMO. On the other hand, ATM is important for TAK1 activation and TRAF6 poly-ubiquitination, two steps necessary for full IKK complex activation too. The present work therefore highlighted a third ATM-mediated NF-κB regulation mechanism. This study showed that following DNA damage, the phosphorylation of p65 on Ser547 by ATM lead to the lower expression of a set of specific genes mainly involved in inflammation. Phosphorylated p65 was shown to interact with the co-repressor HDAC1, leading to specific promoter deacetylation and subsequent decreased gene expression.   In a second time, we also showed for the first time the requirement of MDC1 protein in DNA damage-induced NF-κB activation. MDC1 protein is mainly described as playing an important role in DSB-induced nuclear foci, which consist in large protein structures that assemble at the site of the DSB. Nevertheless, it appeared in this study that the role of MDC1 in NF-κB activation pathway is foci-independent.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Sabatel, Hélène ;  Université de Liège - ULiège > GIGA-R : Virologie - Immunologie
Language :
English
Title :
Role of NF-κB p65 subunit phosphorylation by ATM in DNA damage-regulated gene expression
Defense date :
2012
Institution :
ULiège - Université de Liège
Degree :
docteur en sciences
Promotor :
Habraken, Yvette ;  Université de Liège - ULiège > GIGA > GIGA Molecular Biology of Diseases - Gene Expression & Cancer
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since 07 November 2012

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