Defects in homologous recombination repair in mismatch-repair-deficient tumour cell lines
Defects in homologous recombination repair in mismatch-repair-deficient tumour cell lines
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DOI：
10.1093/hmg/11.18.2189
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发表时间：
2002-09-01
影响因子：
3.5
通讯作者：
Meuth, M
中科院分区：
文献类型：
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作者：
Mohindra, A;Hays, LE;Meuth, M
失配修复（MMR）导致复杂的突变表型，这似乎驱动了结肠癌子集的发展。在这里，我们表明，相对于mmr熟练的细胞系，mmr缺陷的肿瘤细胞系对胸腺嘧啶的毒性作用高度敏感。这种敏感性不是MMR缺乏或DNA前体代谢改变的直接后果。相反，mmr缺陷的肿瘤细胞系在DNA双链断裂诱导的同源重组修复（HRR）中也存在缺陷。此外，在mmr缺陷子宫肿瘤细胞系SKUT-1中发现的人类RAD51平行XRCC2的移码突变，当引入mmr精通细胞系时，可以赋予胸苷嘧啶敏感性。与其他XRCC2有缺陷的细胞一样，SKUT-1对丝裂霉素C敏感，表达突变XRCC2等位基因的mmr熟练细胞对这种药物更敏感。这些数据表明mmr缺陷肿瘤细胞系胸苷敏感性可能是HRR通路缺陷的结果。胸腺嘧啶敏感性的增加和DNA双链断裂修复重要途径的缺失，为专门针对这类肿瘤的治疗创造了新的机会。
Loss of mismatch repair (MMR) leads to a complex mutator phenotype that appears to drive the development of a subset of colon cancers. Here we show that MMR-deficient tumour cell lines are highly sensitive to the toxic effects of thymidine relative to MMR-proficient lines. This sensitivity was not a direct consequence of MMR deficiency or alterations of DNA precursor metabolism. Instead, MMR-defective tumour cell lines are also defective in homologous recombination repair (HRR) induced by DNA double-strand breaks. Furthermore, a frameshift mutation of the human RAD51 paralog XRCC2 found in the MMR-deficient uterine tumour cell line SKUT-1 can confer thymidine sensitivity when introduced into a MMR-proficient line. Like other cells with defective XRCC2, SKUT-1 is sensitive to mitomycin C, and MMR-proficient cells expressing the mutant XRCC2 allele become more sensitive to this agent. These data suggest that the thymidine sensitivity of MMR-deficient tumour cell lines may be a consequence of defects in the HRR pathway. The increased thymidine sensitivity and the loss of an important pathway for the repair of DNA double-strand breaks create new opportunities for therapies directed specifically against this subset of tumours.