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Chromatin assembly factors and heterochromatin organization during cell prolifertaion, tumorigenesis and in quiescence

Abstract : In cancer cells, the organization of DNA in chromatin is frequently affected. Thus, it is crucial to understand how factors involved in chromatin organization contribute to tumorigenesis. Of particular interest in this context is the Chromatin Assembly Factor 1 (CAF-1). CAF-1 is a complex involved in chromatin assembly coupled to DNA synthesis, both during DNA replication and DNA repair. Two subunits of the CAF-1 complex are downregulated in quiescent cells and can be used as proliferation markers in cancer cells. In addition, CAF-1 has a role in the maintenance of the compact chromatin domains near the centromeres, called pericentric heterochromatin, through its interaction with Heterochromatin Protein 1 (HP1). Three HP1 isoforms (HP1α, β et γ) exist in mammalian cells, among which HP1α associates most specifically with pericentric heterochromatin regions. During my PhD, I have addressed two main questions: First, how do the three human HP1 isoforms relate to cell proliferation and tumorigenesis? Using both cell line models and tumoral and healthy human tissue samples, I showed that the expression of HP1α isoform, but not HP1β ou γ, is proliferation-dependent. Downregulation of HP1α, specifically, results in mitotic defects. In addition, HP1α, but not HP1β ou γ, is overexpressed in several tumoral tissues compared to the corresponding healthy tissues. In breast cancer, the level of HP1α overexpression significantly correlates with global survival and the occurence of metastasis. Our results suggest that HP1α overexpression confers a growth advantage to tumor cells that is related to the organization of pericentric heterochromatin and the passage of mitosis. We put forward HP1α as new prognostic marker in breast cancer and potentially other cancers. This study gave rise to the deposition of a patent and a publication in EMBO Molecular Medecine. The second main question I have addressed is: how do quiescent cells, which express CAF-1 at very low levels, deal with chromatin assembly coupled to DNA repair? This question is of particular interest since a differential repair capacity between tumoral (proliferative) cells and healthy (quiescent) cells will affect the efficiency and the toxicity of genotoxic cancer treatments, such as chemo- and radiotherapy Using ultra-violet (UV) irradiation as a means to induce DNA lesions, I was able to show that CAF-1 expression is not induced upon DNA damage and that the low levels of CAF-1 are sufficient for its recruitment to sites of UV lesions, suggesting that its function is conserved in quiescence. However, we observe a delayed repair of a specific type of UV lesions in quiescence. Our results suggest that the repair of these lesions might require additional chromatin dynamics, which would be the limiting step in quiescence, potentially due to the extremely low levels of CAF-1. These observations gave rise to a manuscript that is currently in preparation. In these two major projects, I have demonstrated how factors involved in chromatin organization are related to cell proliferation, tumorigenesis and, more generally, genome stability. In addition, we have been able to put forward a new marker of clinical interest for breast cancer prognosis.
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Leanne de Koning. Chromatin assembly factors and heterochromatin organization during cell prolifertaion, tumorigenesis and in quiescence. Cellular Biology. Université Pierre et Marie Curie - Paris VI, 2009. English. ⟨NNT : 2009PA066467⟩. ⟨tel-00814265⟩

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