Polymerization by DNA polymerase η is blocked by cis-diamminedichloroplatinum(II) 1,3-d(GpTpG) cross-link: implications for cytotoxic effects in nucleotide excision repair-negative tumor cells
Polymerization by DNA polymerase η is blocked by cis-diamminedichloroplatinum(II) 1,3-d(GpTpG) cross-link: implications for cytotoxic effects in nucleotide excision repair-negative tumor cells
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DOI：
10.1093/carcin/bgp316
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发表时间：
2010-03-01
期刊：
影响因子：
4.7
通讯作者：
Kuraoka, Isao
中科院分区：
文献类型：
--
作者：
Chijiwa, Shotaro;Masutani, Chikahide;Kuraoka, Isao
顺二氨二氯铂（II）（顺铂）形成DNA加合物，干扰复制和转录。体内形成的最常见的加合物是1，2-链内d（GpG）交联（Pt-GG）和d（ApG）交联（Pt-AG），以及少量的1，3-d（GpNpG）交联（Pt-GNG）、链间交联和单加合物。虽然这些不同加合物对毒性的相对贡献尚不清楚，但文献表明Pt-GG和Pt-AG加合物可阻断复制。因此，核苷酸切除修复（NER），其中铂加合物被切除，和translesion DNA合成（TLS），允许加合物旁路，被认为是与顺铂耐药。最近的研究报道，如果肿瘤细胞表达低水平的NER因子，则基于铂的化疗的临床益处高。为了研究铂-DNA加合物在TLS介导肿瘤细胞存活中的作用，我们检查了可能存在于NER阴性肿瘤细胞中但不存在于NER阳性肿瘤细胞中的1，3-链内d（GpTpG）铂交联（Pt-GTG）是否被跨病变DNA聚合酶eta（pol eta）绕过，该聚合酶已知绕过Pt-GG。我们表明，聚合物可以掺入正确的脱氧胞苷三磷酸相对的第一个3 '-交联的G的Pt-GTG，但不能插入任何核苷酸相对的第二个完整的T或第三个5'-交联的G的加合物，从而表明TLS不促进复制过去的Pt-GTG加合物。因此，我们的研究结果暗示Pt-GNG加合物介导了体内NER阴性肿瘤中铂-DNA加合物的细胞毒性。
cis-Diamminedichloroplatinum(II) (cisplatin) forms DNA adducts that interfere with replication and transcription. The most common adducts formed in vivo are 1,2-intrastrand d(GpG) cross-links (Pt-GG) and d(ApG) cross-links (Pt-AG), with minor amounts of 1,3-d(GpNpG) cross-links (Pt-GNG), interstrand cross-links and monoadducts. Although the relative contribution of these different adducts to toxicity is not known, literature implicates that Pt-GG and Pt-AG adducts block replication. Thus, nucleotide excision repair (NER), by which platinum adducts are excised, and translesion DNA synthesis (TLS), which permits adduct bypass, are thought to be associated with cisplatin resistance. Recent studies have reported that the clinical benefit from platinum-based chemotherapy is high if tumor cells express low levels of NER factors. To investigate the role of platinum-DNA adducts in mediating tumor cell survival by TLS, we examined whether 1,3-intrastrand d(GpTpG) platinum cross-links (Pt-GTG), which probably exist in NER-negative tumor cells but not in NER-positive tumor cells, are bypassed by the translesion DNA polymerase eta (pol eta), which is known to bypass Pt-GG. We show that pol eta can incorporate the correct deoxycytidine triphosphate opposite the first 3'-cross-linked G of Pt-GTG but cannot insert any nucleotides opposite the second intact T or the third 5'-cross-linked G of the adducts, thereby suggesting that TLS does not facilitate replication past Pt-GTG adducts. Thus, our findings implicate Pt-GNG adducts as mediating the cytotoxicity of platinum-DNA adducts in NER-negative tumors in vivo.