A role for polymerase η in the cellular tolerance to cisplatin-induced damage
A role for polymerase η in the cellular tolerance to cisplatin-induced damage
复制标题
DOI：
10.1158/0008-5472.can-05-1095
复制
发表时间：
2005-11-01
期刊：
影响因子：
11.2
通讯作者：
O'Connor, MJ
中科院分区：
文献类型：
--
作者：
Albertella, MR;Green, CM;O'Connor, MJ
编码DNA聚合酶eta（pol eta）的POLH基因突变导致UV敏感综合征着色性干皮病变体（XP-V），这与pol eta在称为translesion合成的过程中准确绕过UV诱导的环丁烷嘧啶二聚体的能力有关。Pol eta也可以在体外绕过其他DNA损伤加合物，包括顺铂诱导的链内加合物，尽管其生理相关性尚不清楚。在这里，我们表明，独立的XP-V细胞系是显着更敏感的顺铂比相同的细胞补充功能多。用化疗剂卡铂和奥沙利铂获得了类似的结果，从而揭示了在提供对这些基于铂的药物的耐受性中对pol eta表达的一般要求。观察到的致敏水平与核苷酸切除修复缺陷的XP-A细胞相当，核苷酸切除修复是修复顺铂加合物的公认的重要机制。然而，与XP-A细胞不同，pol eta表达的缺乏导致克服顺铂诱导的S期阻滞的能力降低，表明pol eta参与了这些复制阻断加合物的跨损伤合成。亚细胞定位研究还强调了与顺铂治疗后单泛素化增殖细胞核抗原的形成相关的具有pol eta病灶的细胞核的积累，这让人想起对UV照射的反应，并进一步表明pol eta在处理顺铂诱导的损伤中的作用。总之，这些数据表明，pol eta代表了细胞对顺铂反应的重要决定因素，这可能对这种关键化疗药物的获得性或内在抗性有影响。
Mutation of the POLH gene encoding DNA polymerase eta (pol eta) causes the UV-sensitivity syndrome xeroderma pigmentosum-variant (XP-V) which is linked to the ability of pol eta to accurately bypass UV-induced cyclobutane pyrimidine dimers during a process termed translesion synthesis. Pol eta can also bypass other DNA damage adducts in vitro, including cisplatin-induced intrastrand adducts, although the physiological relevance of this is unknown. Here, we show that independent XP-V cell lines are dramatically more sensitive to cisplatin than the same cells complemented with functional pol eta. Similar results were obtained with the chemotherapeutic agents, carboplatin and oxaliplatin, thus revealing a general requirement for pol eta expression in providing tolerance to these platinum-based drugs. The level of sensitization observed was comparable to that of XP-A cells deficient in nucleotide excision repair, a recognized and important mechanism for repair of cisplatin adducts. However, unlike in XP-A cells, the absence of pol eta expression resulted in a reduced ability to overcome cisplatin-induced S phase arrest, suggesting that pol eta is involved in translesion synthesis past these replication-blocking adducts. Subcellular localization studies also highlighted an accumulation of nuclei with pol eta foci that correlated with the formation of monoubiquitinated proliferating cell nuclear antigen following treatment with cisplatin, reminiscent of the response to UV irradiation and further indicating a role for pol eta in dealing with cisplatin-induced damage. Together, these data show that pol eta represents an important determinant of cellular responses to cisplatin, which could have implications for acquired or intrinsic resistance to this key chemotherapeutic agent.