XLF Interacts with the XRCC4-DNA Ligase IV Complex to Promote DNA Nonhomologous End-Joining
| Autor: | Stephen P. Jackson, Peter Ahnesorg, Philippa Smith |
|---|---|
| Jazyk: | angličtina |
| Předmět: |
chemistry.chemical_classification
0303 health sciences Mutation DNA ligase Biochemistry Genetics and Molecular Biology(all) DNA repair LIG4 syndrome Biology DNA repair protein XRCC4 LIG4 medicine.disease_cause medicine.disease Molecular biology General Biochemistry Genetics and Molecular Biology Non-homologous end joining 03 medical and health sciences DNA ligase IV complex enzymes and coenzymes (carbohydrates) 0302 clinical medicine chemistry 030220 oncology & carcinogenesis embryonic structures medicine 030304 developmental biology |
| Zdroj: | Cell. (2):301-313 |
| ISSN: | 0092-8674 |
| DOI: | 10.1016/j.cell.2005.12.031 |
| Popis: | SummaryDNA nonhomologous end-joining (NHEJ) is a predominant pathway of DNA double-strand break repair in mammalian cells, and defects in it cause radiosensitivity at the cellular and whole-organism levels. Central to NHEJ is the protein complex containing DNA Ligase IV and XRCC4. By searching for additional XRCC4-interacting factors, we identified a previously uncharacterized 33 kDa protein, XRCC4-like factor (XLF, also named Cernunnos), that has weak sequence homology with XRCC4 and is predicted to display structural similarity to XRCC4. We show that XLF directly interacts with the XRCC4-Ligase IV complex in vitro and in vivo and that siRNA-mediated downregulation of XLF in human cell lines leads to radiosensitivity and impaired NHEJ. Furthermore, we establish that NHEJ-deficient 2BN cells derived from a radiosensitive and immune-deficient patient lack XLF due to an inactivating frameshift mutation in its gene, and that reintroduction of wild-type XLF into such cells corrects their radiosensitivity and NHEJ defects. XLF thus constitutes a novel core component of the mammalian NHEJ apparatus. |
| Databáze: | OpenAIRE |
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