The Fanconi anemia group A protein modulates homologous repair of DNA double-strand breaks in mammalian cells Journal Article
| Authors: | Yang, Y. G.; Herceg, Z.; Nakanishi, K.; Demuth, I.; Piccoli, C.; Michelon, J.; Hildebrand, G.; Jasin, M.; Digweed, M.; Wang, Z. Q. |
| Article Title: | The Fanconi anemia group A protein modulates homologous repair of DNA double-strand breaks in mammalian cells |
| Abstract: | Fanconi anemia (FA) cells exhibit hypersensitivity to DNA interstrand cross-links (ICLs) and high levels of chromosome instability. FA gene products have been shown to functionally or physically interact with BRCA1, RAD51 and the MRE11/RAD50/NBS1 complex, suggesting that the FA complex may be involved in the repair of DNA double-strand breaks (DSBs). Here, we have investigated specifically the function of the FA group A protein (FANCA) in the repair of DSBs in mammalian cells. We show that the targeted deletion of Fanca exons 37-39 generates a null for Fanca in mice and abolishes ubiquitination of Fancd2, the downstream effector of the FA complex. Cells lacking Fanca exhibit increased chromosomal aberrations and attenuated accumulation of Brca1 and Rad51 foci in response to DNA damage. The absence of Fanca greatly reduces gene-targeting efficiency in mouse embryonic stem (ES) cells and compromises the survival of fibroblast cells in response to ICL agent treatment. Fanca null cells exhibit compromised homology-directed repair (HDR) of DSBs, particularly affecting the single-strand annealing pathway. These data identify the Fanca protein as an integral component in the early step of HDR of DSBs and thereby minimizing the genomic instability. © Oxford University Press 2005; all rights reserved. |
| Keywords: | signal transduction; controlled study; unclassified drug; exon; gene deletion; dna-binding proteins; exons; sequence deletion; nonhuman; protein function; protein analysis; animal cell; mouse; animals; mice; mice, knockout; dna damage; cell survival; gene targeting; complex formation; dna repair; embryo; embryonic stem cell; cell protein; cell line; brca1 protein; dna strand breakage; chromosome aberration; double stranded dna; ubiquitination; genomic instability; fibroblast; sequence homology; dna cross linking; rad51 protein; downstream processing; chromosome mapping; fanconi anemia; mammal cell; null cell; fanconi anemia group a protein; fanconi anemia complementation group a protein |
| Journal Title: | Carcinogenesis |
| Volume: | 26 |
| Issue: | 10 |
| ISSN: | 0143-3334 |
| Publisher: | Oxford University Press |
| Date Published: | 2005-10-01 |
| Start Page: | 1731 |
| End Page: | 1740 |
| Language: | English |
| DOI: | 10.1093/carcin/bgi134 |
| PUBMED: | 15905196 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 38" - "Export Date: 24 October 2012" - "CODEN: CRNGD" - "Source: Scopus" |
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