Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition
Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition
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DOI：
10.1158/0008-5472.can-06-0140
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发表时间：
2006-08-15
期刊：
影响因子：
11.2
通讯作者：
Ashworth, Alan
中科院分区：
文献类型：
--
作者：
McCabe, Nuala;Turner, Nicholas C.;Ashworth, Alan
乳腺癌易感蛋白BRCA 1或BRCA 2的缺陷诱导细胞对聚（ADP-核糖）聚合酶（PARP）活性抑制的深刻敏感性。我们假设BRCA 1和BRCA 2在同源重组（HR）修复双链断裂中的关键作用是这种敏感性的根本原因。在这里，我们研究了参与HR的几种蛋白质缺乏对PARP抑制的敏感性的影响。我们发现，RAD 51，RAD 54，DSS 1，RPA 1，NBS 1，ATR，ATM，CHK 1，CHK 2，FANCD 2，FANCA或FANCC的缺陷诱导这种敏感性。这表明BRCA缺陷细胞至少部分地由于HR缺陷而对PARP抑制敏感。这些结果表明，PARP抑制可能是一种有用的治疗策略，不仅可用于治疗BRCA突变相关肿瘤，而且可用于治疗在HR途径中具有各种缺陷或显示“BRCA阴性”特性的更广泛的肿瘤。'
Deficiency in either of the breast cancer susceptibility proteins BRCA1 or BRCA2 induces profound cellular sensitivity to the inhibition of poly(ADP-ribose) polymerase (PARP) activity. We hypothesized that the critical role of BRCA1 and BRCA2 in the repair of double-strand breaks by homologous recombination (HR) was the underlying reason for this sensitivity. Here, we examine the effects of deficiency of several proteins involved in HR on sensitivity to PARP inhibition. We show that deficiency of RAD51, RAD54, DSS1, RPA1, NBS1, ATR, ATM, CHK1, CHK2, FANCD2, FANCA, or FANCC induces such sensitivity. This suggests that BRCA-deficient cells are, at least in part, sensitive to PARP inhibition because of HR deficiency. These results indicate that PARP inhibition might be a useful therapeutic strategy not only for the treatment of BRCA mutation-associated tumors but also for the treatment of a wider range of tumors bearing a variety of deficiencies in the HR pathway or displaying properties of 'BRCAness.'