Hierarchy of lesion processing governs the repair, double-strand break formation and mutability of three-lesion clustered DNA damage.
Hierarchy of lesion processing governs the repair, double-strand break formation and mutability of three-lesion clustered DNA damage.
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DOI：
10.1093/nar/gkp1070
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发表时间：
2010-03
影响因子：
14.9
通讯作者：
O'Neill P
中科院分区：
文献类型：
--
作者：
Eccles LJ;Lomax ME;O'Neill P
电离辐射会诱导聚集的 DNA 损伤位点，这对细胞的修复机制，特别是碱基切除修复提出了严峻的挑战。迄今为止，大多数研究都集中在两个病变群上。我们设计了合成寡核苷酸来提供各种含有脱碱基位点和 8-oxo-7, 8-二氢鸟嘌呤的三损伤簇，以研究损伤处理的层次结构是否决定该簇是否具有细胞毒性或致突变性。包含与 AP 位点相对的两个串联 8-oxoG 损伤的簇显示出核提取物对 AP 位点的修复延迟，并且在转化为野生型或突变型大肠杆菌后突变频率升高。含有双链 AP 位点和邻位 8-oxoG 的簇与核提取物形成 DSB，通过转化到野生型大肠杆菌体内证实了这一点。使用ung1大肠杆菌，我们提出DSB是通过病变处理而不是循环细胞中的复制停滞而产生的。这项研究提供的证据表明，不仅 DSB 的迅速形成对细胞存活有影响，而且在加工和尝试修复过程中非 DSB 簇也会转化为 DSB。由于肿瘤发生的最终风险或肿瘤细胞中潜在的细胞毒性病变，此类簇的不准确修复具有生物学意义。
Ionising radiation induces clustered DNA damage sites which pose a severe challenge to the cell’s repair machinery, particularly base excision repair. To date, most studies have focussed on two-lesion clusters. We have designed synthetic oligonucleotides to give a variety of three-lesion clusters containing abasic sites and 8-oxo-7, 8-dihydroguanine to investigate if the hierarchy of lesion processing dictates whether the cluster is cytotoxic or mutagenic. Clusters containing two tandem 8-oxoG lesions opposing an AP site showed retardation of repair of the AP site with nuclear extract and an elevated mutation frequency after transformation into wild-type or mutY Escherichia coli. Clusters containing bistranded AP sites with a vicinal 8-oxoG form DSBs with nuclear extract, as confirmed in vivo by transformation into wild-type E. coli. Using ung1 E. coli, we propose that DSBs arise via lesion processing rather than stalled replication in cycling cells. This study provides evidence that it is not only the prompt formation of DSBs that has implications on cell survival but also the conversion of non-DSB clusters into DSBs during processing and attempted repair. The inaccurate repair of such clusters has biological significance due to the ultimate risk of tumourigenesis or as potential cytotoxic lesions in tumour cells.
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DOI：
10.1073/pnas.131077798
发表时间：
2001-06-19
影响因子：
11.1
作者：
Blaisdell, JO;Wallace, SS
通讯作者：
Wallace, SS
影响因子：
2.6
作者：
GOODHEAD, DT
通讯作者：
GOODHEAD, DT
DOI：
10.1073/pnas.062053799
发表时间：
2002-03-19
影响因子：
11.1
作者：
Hazra, TK;Izumi, T;Mitra, S
通讯作者：
Mitra, S
影响因子：
14.9
作者：
Eot-Houllier G;Eon-Marchais S;Gasparutto D;Sage E
通讯作者：
Sage E
影响因子：
2.9
作者：
David-Cordonnier, MH;Cunniffe, SMT;O'Neill, P
通讯作者：
O'Neill, P