The Xpc gene markedly affects cell survival in mouse bone marrow.
The Xpc gene markedly affects cell survival in mouse bone marrow.
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DOI：
10.1093/mutage/gep011
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发表时间：
2009-07
期刊：
影响因子：
2.7
通讯作者：
Smith ML
中科院分区：
文献类型：
--
作者：
Fischer JL;Kumar MA;Day TW;Hardy TM;Hamilton S;Besch-Williford C;Safa AR;Pollok KE;Smith ML
XPC蛋白（由着色性干皮病Xpc基因编码）是一种关键的DNA损伤识别因子，是全局基因组核苷酸切除修复（G-NER）所需的。与转录偶联核苷酸切除修复（TC-NER）相反，据报道XPC和G-NER仅对DNA损伤后的细胞存活有适度的贡献。先前的研究使用人或小鼠来源的成纤维细胞进行。自从Xpc−/−小鼠出现以来，没有研究关注这些小鼠的骨髓。我们使用卡铂在Xpc−/−和品系匹配的野生型小鼠中诱导DNA损伤。使用几种独立的方法，Xpc−/−骨髓对卡铂的敏感性是野生型的10倍。重要的是，12/20的Xpc−/−小鼠死亡，而0/20的野生型小鼠死亡。我们的结论是，G-NER，特别是XPC，可以大大有助于细胞存活。这些数据在癌症化疗的背景下是重要的，其中Xpc基因状态和G-NER可能是对包括卡铂在内的DNA损伤剂的反应的决定因素。此外，改变的细胞周期和改变的DNA损伤信号可能有助于细胞存活终点。
The XPC protein (encoded by the xeroderma pigmentosum Xpc gene) is a key DNA damage recognition factor that is required for global genomic nucleotide excision repair (G-NER). In contrast to transcription-coupled nucleotide excision repair (TC-NER), XPC and G-NER have been reported to contribute only modestly to cell survival after DNA damage. Previous studies were conducted using fibroblasts of human or mouse origin. Since the advent of Xpc−/− mice, no study has focused on the bone marrow of these mice. We used carboplatin to induce DNA damage in Xpc−/− and strain-matched wild-type mice. Using several independent methods, Xpc−/− bone marrow was ∼10-fold more sensitive to carboplatin than the wild type. Importantly, 12/20 Xpc−/− mice died while 0/20 wild-type mice died. We conclude that G-NER, and XPC specifically, can contribute substantially to cell survival. The data are important in the context of cancer chemotherapy, where Xpc gene status and G-NER may be determinants of response to DNA-damaging agents including carboplatin. Additionally, altered cell cycles and altered DNA damage signalling may contribute to the cell survival end point.
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