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Base Excision by Thymine DNA Glycosylase Mediates DNA-Directed Cytotoxicity of 5-Fluorouracil

หน่วยงาน Edinburgh Research Archive, United Kingdom

รายละเอียด

ชื่อเรื่อง : Base Excision by Thymine DNA Glycosylase Mediates DNA-Directed Cytotoxicity of 5-Fluorouracil
นักวิจัย : Selfridge J. , Schar P. , Lettieri T. , Schuermann D. , Saito Y. , Focke F. , Kunz C.
คำค้น : cancer cell-lines; thymidylate synthase; repair enzyme; damage response; n-glycosylase; comet assay; med1 mbd4; s-phase; uracil; mechanism
หน่วยงาน : Edinburgh Research Archive, United Kingdom
ผู้ร่วมงาน : -
ปีพิมพ์ : 2552
อ้างอิง : Selfridge J., Schar P., Lettieri T., Schuermann D.. (2009-04-01) Base Excision by Thymine DNA Glycosylase Mediates DNA-Directed Cytotoxicity of 5-Fluorouracil, PLOS Biology 7(4) 967-979 , 1544-9173 , http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1000091 , http://dx.doi.org/10.1371/journal.pbio.1000091 , http://hdl.handle.net/1842/3029
ที่มา : -
ความเชี่ยวชาญ : -
ความสัมพันธ์ : -
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บทคัดย่อ/คำอธิบาย :

5-Fluorouracil (5-FU), a chemotherapeutic drug commonly used in cancer treatment, imbalances nucleotide pools, thereby favoring misincorporation of uracil and 5-FU into genomic DNA. The processing of these bases by DNA repair activities was proposed to cause DNA-directed cytotoxicity, but the underlying mechanisms have not been resolved. In this study, we investigated a possible role of thymine DNA glycosylase (TDG), one of four mammalian uracil DNA glycosylases (UDGs), in the cellular response to 5-FU. Using genetic and biochemical tools, we found that inactivation of TDG significantly increases resistance of both mouse and human cancer cells towards 5-FU. We show that excision of DNA-incorporated 5-FU by TDG generates persistent DNA strand breaks, delays S-phase progression, and activates DNA damage signaling, and that the repair of 5-FU-induced DNA strand breaks is more efficient in the absence of TDG. Hence, excision of 5-FU by TDG, but not by other UDGs (UNG2 and SMUG1), prevents efficient downstream processing of the repair intermediate, thereby mediating DNA-directed cytotoxicity. The status of TDG expression in a cancer is therefore likely to determine its response to 5-FU-based chemotherapy.

บรรณานุกรม :
Selfridge J. , Schar P. , Lettieri T. , Schuermann D. , Saito Y. , Focke F. , Kunz C. . (2552). Base Excision by Thymine DNA Glycosylase Mediates DNA-Directed Cytotoxicity of 5-Fluorouracil.
    กรุงเทพมหานคร : Edinburgh Research Archive, United Kingdom .
Selfridge J. , Schar P. , Lettieri T. , Schuermann D. , Saito Y. , Focke F. , Kunz C. . 2552. "Base Excision by Thymine DNA Glycosylase Mediates DNA-Directed Cytotoxicity of 5-Fluorouracil".
    กรุงเทพมหานคร : Edinburgh Research Archive, United Kingdom .
Selfridge J. , Schar P. , Lettieri T. , Schuermann D. , Saito Y. , Focke F. , Kunz C. . "Base Excision by Thymine DNA Glycosylase Mediates DNA-Directed Cytotoxicity of 5-Fluorouracil."
    กรุงเทพมหานคร : Edinburgh Research Archive, United Kingdom , 2552. Print.
Selfridge J. , Schar P. , Lettieri T. , Schuermann D. , Saito Y. , Focke F. , Kunz C. . Base Excision by Thymine DNA Glycosylase Mediates DNA-Directed Cytotoxicity of 5-Fluorouracil. กรุงเทพมหานคร : Edinburgh Research Archive, United Kingdom ; 2552.