ATM damage response and XLF repair factor are functionally redundant in joining DNA breaks
| Autor: | Duane R. Wesemann, Richard L. Dubois, Valentyn Oksenych, Yu Zhang, Hwei-Ling Cheng, Harin Patel, Cristian Boboila, Chunguang Guo, Peter H. Goff, Frederick W. Alt, Grace J. Yuen, Shan Zha |
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| Rok vydání: | 2010 |
| Předmět: |
DNA Repair
DNA repair Cell Cycle Proteins Ataxia Telangiectasia Mutated Proteins Protein Serine-Threonine Kinases LIG4 DNA-binding protein Article Histones Mice 03 medical and health sciences 0302 clinical medicine Animals DNA Breaks Double-Stranded Gene Rearrangement B-Lymphocyte Cell Line Transformed 030304 developmental biology Recombination Genetic 0303 health sciences Multidisciplinary biology Precursor Cells B-Lymphoid Tumor Suppressor Proteins DNA repair protein XRCC4 Embryo Mammalian Chromosomes Mammalian Molecular biology Chromatin DNA-Binding Proteins Non-homologous end joining enzymes and coenzymes (carbohydrates) Histone Immunoglobulin class switching 030220 oncology & carcinogenesis biology.protein |
| Zdroj: | Nature |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/nature09604 |
| Popis: | The loss of a classical non-homologous end-joining (NHEJ) repair factor, XLF, shows strong effects in non-lymphoid cells, but in lymphoid cells its absence surprisingly has only modest effects on V(D)J recombination. Frederick Alt and colleagues show that in lymphoid cells, two other repair factors — ATM kinase and histone protein H2AX — have functional redundancy with XLF. Thus, mice that are deficient in both ATM and XLF have compromised conventional NHEJ, although alternative end-joining is retained. The results hint that the redundant function in end-joining that XLF has with both ATM and H2AX may be related to a role for ATM in chromatin accessibility. Although loss of XLF, a classical non-homologous DNA end-joining (NHEJ) repair factor, shows strong effects in non-lymphoid cells, in lymphoid cells its absence has only modest effects on V(D)J recombination. This study now shows that in lymphoid cells, two other repair factors — ATM kinase and histone protein H2AX — have functional redundancy with XLF. Thus, mice deficient in both ATM and XLF have compromised conventional NHEJ, although alternative end-joining is retained. The results hint that the redundant function in end-joining that XLF has with both ATM and H2AX may have to do with an ATM role in chromatin accessibility. Classical non-homologous DNA end-joining (NHEJ) is a major mammalian DNA double-strand-break (DSB) repair pathway. Deficiencies for classical NHEJ factors, such as XRCC4, abrogate lymphocyte development, owing to a strict requirement for classical NHEJ to join V(D)J recombination DSB intermediates1,2. The XRCC4-like factor (XLF; also called NHEJ1) is mutated in certain immunodeficient human patients and has been implicated in classical NHEJ3,4,5,6; however, XLF-deficient mice have relatively normal lymphocyte development and their lymphocytes support normal V(D)J recombination5. The ataxia telangiectasia-mutated protein (ATM) detects DSBs and activates DSB responses by phosphorylating substrates including histone H2AX7. However, ATM deficiency causes only modest V(D)J recombination and lymphocyte developmental defects, and H2AX deficiency does not have a measurable impact on these processes7,8,9. Here we show that XLF, ATM and H2AX all have fundamental roles in processing and joining DNA ends during V(D)J recombination, but that these roles have been masked by unanticipated functional redundancies. Thus, combined deficiency of ATM and XLF nearly blocks mouse lymphocyte development due to an inability to process and join chromosomal V(D)J recombination DSB intermediates. Combined XLF and ATM deficiency also severely impairs classical NHEJ, but not alternative end-joining, during IgH class switch recombination. Redundant ATM and XLF functions in classical NHEJ are mediated by ATM kinase activity and are not required for extra-chromosomal V(D)J recombination, indicating a role for chromatin-associated ATM substrates. Correspondingly, conditional H2AX inactivation in XLF-deficient pro-B lines leads to V(D)J recombination defects associated with marked degradation of unjoined V(D)J ends, revealing that H2AX has a role in this process. |
| Databáze: | OpenAIRE |
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