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Étude du rôle des facteurs MYSM1 et ZNF699 dans la réparation de l'ADN

Abstract : For the last 20 years, important knowledge were acquired regarding the implication of the DNA damage response (DDR) in the development, maturation and function of the immune system. The lab DGSI has shown that DNA repair deficiencies can lead to immune disorders and in some cases to cancer predisposition. The first part of this thesis is based on the study of a patient exhibiting an immune deficiency and developmental problems. An homozygous misense mutation affecting the catalytic site of the protein MYSM1 was identified for this patient. MYSM1 is a metalloprotease, targeting monoubiquitinated histone H2A on lysine 119 (H2AK119ub), a marker of transcription silencing. Based on murine models, MYSM1 was described as a transcriptional derepresser of genes implicated in hematopoietic stem cells homeostasis and lymphocytes differentiation. The MYSM1 deficient patient suffered from a complete absence of B cells, a T cell lymhopenia, some hematopoietic defects and developmental abnormalities. As observed in the murine model, those symptoms could be explained by a transcriptional deregulation of factors implicated in the immuno-hematopoietic development. However, patient's fibroblasts are hypersensitive to certain genotoxic compounds. Hence, the DDR seems to be impaired in the patient cells, which is not described in murine models, and suggests an implication of MYSM1 in the DDR. A second part of the thesis focuses on ZNF699, wich is a zinc finger protein. An homozygous insertion of one nucleotide, leading to a frameshift, was identified in the gene coding for ZNF699 in a patient suffering from medullar aplasia, accelerated aging and short telomeres. Cells from this patient are also hypersensitive to some gentoxic compounds, suggesting the implication of ZNF699 in the DDR. The aim of this work is to understand the role of these two factors MYSM1 and ZNF699 in each patient pathology, and decipher their respective implication in the DDR.
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Submitted on : Wednesday, March 18, 2020 - 12:08:10 PM
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Benoît France. Étude du rôle des facteurs MYSM1 et ZNF699 dans la réparation de l'ADN. Biologie cellulaire. Université Sorbonne Paris Cité, 2018. Français. ⟨NNT : 2018USPCB072⟩. ⟨tel-02510917⟩



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