顺铂及其类似物是目前癌症化学治疗的支柱。1978年，它获美国食品药品监督管理局（FDA）批准用于癌症治疗，现已用于治疗从卵巢癌、子宫癌到非小细胞肺癌等多种癌症类型。
顺铂通过阻碍DNA复制和转录等过程来促使癌细胞凋亡。铂原子与鸟嘌呤的N7共价结合形成1，2链内交联，阻碍DNA聚合酶 (Pol-α ， Pol- δ 和Pol- ε )复制而迫使DNA合成停止。
然而，临床上顺铂治疗癌症最大的问题是发生肿瘤耐受。即癌细胞能应付化学治疗时形成的cisplatin–DNA adducts而继续复制DNA，其中DNA聚合酶η（Pol-η）起着决定性的作用。
目前，美研究人员在线发表了题为《Structural basis for cisplatin DNA damage tolerance by human polymerase η during cancer chemotherapy》的研究论文，阐明了人类细胞中的Pol-η是如何耐受顺铂治疗癌症引起的DNA损伤。该研究论文发表在Nature Structural & Molecular Biology 上。
本研究中呈现了人类Pol-η 在铂原子与鸟嘌呤的N7共价结合形成链内交联的对面插入脱氧胞苷三磷酸(dCTP)的分子结构。研究表明Pol- η对 PtGpG的特异性源自一个活性位点，该活性位点允许发生几何学上符合Watson-Crick的PtGpG -dCTP碱基互补配对和容纳DNA损伤，毫无空间位阻。这个特异性被与PtGpG相互作用的Gln38和Ser62和与新生dCTP相互作用的Arg61增强。
该结构不仅为理解人类细胞中Pol-η如何耐受顺铂治疗引起的DNA损伤提供了基础，而且为癌症治疗中抑制剂的设计提供了框架。（生物谷 Bioon.com)
doi：10.1038/nsmb.2295
PMC:
PMID:
Structural basis for cisplatin DNA damage tolerance by human polymerase η during cancer chemotherapy
Ajay Ummat， Olga Rechkoblit， Rinku Jain， Jayati Roy Choudhury， Robert E Johnson， Timothy D Silverstein， Angeliki Buku， Samer Lone， Louise Prakash， Satya Prakash & Aneel K Aggarwal
Department of Structural and Chemical Biology， Mount Sinai School of Medicine， New York， New York， USA.
Ajay Ummat， Olga Rechkoblit， Rinku Jain， Timothy D Silverstein， Angeliki Buku， Samer Lone & Aneel K Aggarwal
Department of Biochemistry and Molecular Biology， University of Texas Medical Branch， Galveston， Texas， USA.
Jayati Roy Choudhury， Robert E Johnson， Louise Prakash & Satya Prakash
Abstract
A major clinical problem in the use of cisplatin to treat cancers is tumor resistance. DNA polymerase η (Pol-η) is a crucial polymerase that allows cancer cells to cope with the cisplatin–DNA adducts that are formed during chemotherapy. We present here a structure of human Pol-η inserting deoxycytidine triphosphate (dCTP) opposite a cisplatin intrastrand cross-link (PtGpG). We show that the specificity of human Pol-η for PtGpG derives from an active site that is open to permit Watson-Crick geometry of the nascent PtGpG-dCTP base pair and to accommodate the lesion without steric hindrance. This specificity is augmented by the residues Gln38 and Ser62， which interact with PtGpG， and Arg61， which interacts with the incoming dCTP. Collectively， the structure provides a basis for understanding how Pol-η in human cells can tolerate the DNA damage caused by cisplatin chemotherapy and offers a framework for the design of inhibitors in cancer therapy.
