Loss of CHK1 function impedes DNA damage-induced FANCD2 monoubiquitination but normalizes the abnormal G2 arrest in Fanconi anemia
| Autor: | Jean-Hugues Guervilly, Filippo Rosselli, Gaëtane Mace-Aime |
|---|---|
| Přispěvatelé: | Génomes et cancer (GC (FRE2939)), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2007 |
| Předmět: |
environment and public health
chemistry.chemical_compound 0302 clinical medicine Fanconi anemia hemic and lymphatic diseases MESH: RNA Small Interfering Monoubiquitination RNA Small Interfering Luciferases Genetics (clinical) 0303 health sciences Lymphoblast Fanconi Anemia Complementation Group D2 Protein General Medicine Cell biology Crosstalk (biology) 030220 oncology & carcinogenesis Phosphorylation biological phenomena cell phenomena and immunity G2 Phase MESH: Enzyme Activation [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT] animal structures DNA damage Biology MESH: Fanconi Anemia Complementation Group D2 Protein Transfection Models Biological 03 medical and health sciences FANCD2 Genetics medicine Humans Molecular Biology MESH: Protein Kinases 030304 developmental biology MESH: DNA Damage MESH: Humans MESH: Transfection MESH: Models Biological Ubiquitination medicine.disease Molecular biology MESH: Hela Cells Enzyme Activation enzymes and coenzymes (carbohydrates) MESH: Fanconi Anemia MESH: G2 Phase Fanconi Anemia chemistry Checkpoint Kinase 1 MESH: Ubiquitination MESH: Luciferases Protein Kinases DNA DNA Damage HeLa Cells |
| Zdroj: | Human Molecular Genetics Human Molecular Genetics, Oxford University Press (OUP), 2008, 17 (5), pp.679-89. ⟨10.1093/hmg/ddm340⟩ |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | Fanconi anemia (FA) is a cancer-prone hereditary disease resulting from mutations in one of the 13 genes defining the FANC/BRCA pathway. This pathway is involved in the cellular resistance to DNA-cross-linking agents. How the FANC/BRCA pathway is activated and why its deficiency leads to the accumulation of FA cells with a 4N DNA content are still poorly answered questions. We investigated the involvement of ATR pathway members in these processes. We show here that RAD9 and RAD17 are required for DNA interstrand cross-link (ICL) resistance and for the optimal activation of FANCD2. Moreover, we demonstrate that CHK1 and its interacting partner CLASPIN that act downstream in the ATR pathway are required for both FANCD2 monoubiquitination and assembling in subnuclear foci in response to DNA damage. Paradoxically, in the absence of any genotoxic stress, CHK1 or CLASPIN depletion results in an increased basal level of FANCD2 monoubiquitination and focalization. We also demonstrate that the ICL-induced accumulation of FA cells in late S/G2 phase is dependent on ATR and CHK1. In agreement with this, CHK1 phosphorylation is enhanced in FA cells, and chemical inhibition of the ATR/CHK1 axis in FA lymphoblasts decreases their sensitivity to mitomycin C. In conclusion, this work describes a complex crosstalk between CHK1 and the FANC/BRCA pathway: CHK1 activates this pathway through FANCD2 monoubiquitination, whereas FA deficiency leads to a CHK1-dependent G2 accumulation, raising the possibility that the FANC/BRCA pathway downregulates CHK1 activation. |
| Databáze: | OpenAIRE |
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