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Initiation of Genome Instability and Preneoplastic Processes through Loss of Fhit Expression
http://hdl.handle.net/10069/31140
http://hdl.handle.net/10069/31140264c3de1-4fe7-41a3-b6e5-8dc8cd9f9ca3
名前 / ファイル | ライセンス | アクション |
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PLoSGen8_1003077.pdf (1.9 MB)
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Item type | 学術雑誌論文 / Journal Article(1) | |||||
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公開日 | 2013-03-29 | |||||
タイトル | ||||||
タイトル | Initiation of Genome Instability and Preneoplastic Processes through Loss of Fhit Expression | |||||
言語 | ||||||
言語 | eng | |||||
資源タイプ | ||||||
資源タイプ識別子 | http://purl.org/coar/resource_type/c_6501 | |||||
資源タイプ | journal article | |||||
著者 |
Saldivar, Joshua C.
× Saldivar, Joshua C.× Miuma, Satoshi× Bene, Jessica× Hosseini, Seyed Ali× Shibata, Hidetaka× Sun, Jin× Wheeler, Linda J.× Mathews, Christopher K.× Huebner, Kay |
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抄録 | ||||||
内容記述タイプ | Abstract | |||||
内容記述 | Genomic instability drives tumorigenesis, but how it is initiated in sporadic neoplasias is unknown. In early preneoplasias, alterations at chromosome fragile sites arise due to DNA replication stress. A frequent, perhaps earliest, genetic alteration in preneoplasias is deletion within the fragile FRA3B/FHIT locus, leading to loss of Fhit protein expression. Because common chromosome fragile sites are exquisitely sensitive to replication stress, it has been proposed that their clonal alterations in cancer cells are due to stress sensitivity rather than to a selective advantage imparted by loss of expression of fragile gene products. Here, we show in normal, transformed, and cancer-derived cell lines that Fhit-depletion causes replication stress-induced DNA double-strand breaks. Using DNA combing, we observed a defect in replication fork progression in Fhit-deficient cells that stemmed primarily from fork stalling and collapse. The likely mechanism for the role of Fhit in replication fork progression is through regulation of Thymidine kinase 1 expression and thymidine triphosphate pool levels; notably, restoration of nucleotide balance rescued DNA replication defects and suppressed DNA breakage in Fhit-deficient cells. Depletion of Fhit did not activate the DNA damage response nor cause cell cycle arrest, allowing continued cell proliferation and ongoing chromosomal instability. This finding was in accord with in vivo studies, as Fhit knockout mouse tissue showed no evidence of cell cycle arrest or senescence yet exhibited numerous somatic DNA copy number aberrations at replication stress-sensitive loci. Furthermore, cells established from Fhit knockout tissue showed rapid immortalization and selection of DNA deletions and amplifications, including amplification of the Mdm2 gene, suggesting that Fhit loss-induced genome instability facilitates transformation. We propose that loss of Fhit expression in precancerous lesions is the first step in the initiation of genomic instability, linking alterations at common fragile sites to the origin of genome instability. | |||||
書誌情報 |
PLoS Genetics 巻 8, 号 11, p. e1003077, 発行日 2012-11-29 |
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出版者 | ||||||
出版者 | Public Library of Science | |||||
EISSN | ||||||
収録物識別子タイプ | ISSN | |||||
収録物識別子 | 15537404 | |||||
DOI | ||||||
関連タイプ | isIdenticalTo | |||||
識別子タイプ | DOI | |||||
関連識別子 | 10.1371/journal.pgen.1003077 | |||||
権利 | ||||||
権利情報 | © 2012 Saldivar et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | |||||
著者版フラグ | ||||||
出版タイプ | VoR | |||||
出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 | |||||
引用 | ||||||
内容記述タイプ | Other | |||||
内容記述 | PLoS Genetics, 8(11), e1003077; 2012 |