Class switching and meiotic defects in mice lacking the E3 ubiquitin ligase RNF8
| Autor: | André Nussenzweig, Hua Tang Chen, Margarida A. Santos, Nancy Wong, Isaac A. Klein, Junjie Chen, Juan L R Barbancho, Michel C. Nussenzweig, Andrés J. López-Contreras, Oscar Fernandez-Capetillo, Michael S.Y. Huen, Mila Jankovic |
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| Rok vydání: | 2010 |
| Předmět: |
Transcription
Genetic Chromosomal Proteins Non-Histone DNA damage Ubiquitin-Protein Ligases Immunology Ubiquitin-Protein Ligases - deficiency - genetics - physiology 030204 cardiovascular system & hematology Chromatin - metabolism DNA-binding protein Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Ubiquitin Lymphopenia Animals Immunology and Allergy DNA Breaks Double-Stranded RNA Messenger 030304 developmental biology Mice Knockout Recombination Genetic 0303 health sciences biology Brief Definitive Report Intracellular Signaling Peptides and Proteins Immunoglobulin Class Switching - genetics - physiology Cell Biology Immunoglobulin Class Switching Meiosis - genetics - physiology Molecular biology Chromatin 3. Good health Ubiquitin ligase DNA-Binding Proteins Meiosis Histone Immunoglobulin class switching chemistry 030220 oncology & carcinogenesis biology.protein Tumor Suppressor p53-Binding Protein 1 DNA |
| Zdroj: | The Journal of Experimental Medicine The Journal of Cell Biology |
| ISSN: | 1540-9538 0022-1007 |
| DOI: | 10.1084/jem.20092308 |
| Popis: | 53BP1 is a well-known mediator of the cellular response to DNA damage. Two alternative mechanisms have been proposed to explain 53BP1's interaction with DNA double-strand breaks (DSBs), one by binding to methylated histones and the other via an RNF8 E3 ligase-dependent ubiquitylation pathway. The formation of RNF8 and 53BP1 irradiationinduced foci are both dependent on histone H2AX. To evaluate the contribution of the RNF8-dependent pathway to 53BP1 function, we generated RNF8 knockout mice. We report that RNF8 deficiency results in defective class switch recombination (CSR) and accumulation of unresolved immunoglobulin heavy chain-associated DSBs. The CSR DSB repair defect is milder than that observed in the absence of 53BP1 but similar to that found in H2AX-/- mice. Moreover, similar to H2AX but different from 53BP1 deficiency, RNF8-/- males are sterile, and this is associated with defective ubiquitylation of the XY chromatin. Combined loss of H2AX and RNF8 does not cause further impairment in CSR, demonstrating that the two genes function epistatically. Importantly, although 53BP1 foci formation is RNF8 dependent, its binding to chromatin is preserved in the absence of RNF8. This suggests a two-step mechanism for 53BP1 association with chromatin in which constitutive loading is dependent on interactions with methylated histones, whereas DNA damage-inducible RNF8-dependent ubiquitylation allows its accumulation at damaged chromatin. published_or_final_version |
| Databáze: | OpenAIRE |
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