順鉑及其類似物是目前癌癥化學(xué)治療的支柱。1978年,，它獲美國食品藥品監(jiān)督管理局（FDA）批準(zhǔn)用于癌癥治療,，現(xiàn)已用于治療從卵巢癌、子宮癌到非小細(xì)胞肺癌等多種癌癥類型,。
順鉑通過阻礙DNA復(fù)制和轉(zhuǎn)錄等過程來促使癌細(xì)胞凋亡,。鉑原子與鳥嘌呤的N7共價(jià)結(jié)合形成1，2鏈內(nèi)交聯(lián),，阻礙DNA聚合酶 (Pol-α ,， Pol- δ 和Pol- ε )復(fù)制而迫使DNA合成停止。
然而,，臨床上順鉑治療癌癥最大的問題是發(fā)生腫瘤耐受,。即癌細(xì)胞能應(yīng)付化學(xué)治療時(shí)形成的cisplatin–DNA adducts而繼續(xù)復(fù)制DNA，其中DNA聚合酶η（Pol-η）起著決定性的作用,。
目前,，美研究人員在線發(fā)表了題為《Structural basis for cisplatin DNA damage tolerance by human polymerase η during cancer chemotherapy》的研究論文，闡明了人類細(xì)胞中的Pol-η是如何耐受順鉑治療癌癥引起的DNA損傷,。該研究論文發(fā)表在Nature Structural & Molecular Biology 上,。
本研究中呈現(xiàn)了人類Pol-η 在鉑原子與鳥嘌呤的N7共價(jià)結(jié)合形成鏈內(nèi)交聯(lián)的對面插入脫氧胞苷三磷酸(dCTP)的分子結(jié)構(gòu)。研究表明Pol- η對 PtGpG的特異性源自一個(gè)活性位點(diǎn),，該活性位點(diǎn)允許發(fā)生幾何學(xué)上符合Watson-Crick的PtGpG -dCTP堿基互補(bǔ)配對和容納DNA損傷,，毫無空間位阻。這個(gè)特異性被與PtGpG相互作用的Gln38和Ser62和與新生dCTP相互作用的Arg61增強(qiáng),。
該結(jié)構(gòu)不僅為理解人類細(xì)胞中Pol-η如何耐受順鉑治療引起的DNA損傷提供了基礎(chǔ),，而且為癌癥治療中抑制劑的設(shè)計(jì)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.
