靶向DNA修复缺陷的合成致死作用研究进展  

Research progress in synthetic lethality targeting DNA repair defects

作　　者：艾志鹏[1] 贾舒婷[1] 罗瑛[1] 张继虹[1] 

机构地区：[1]昆明理工大学医学院衰老与肿瘤分子遗传学实验室,云南昆明650500

出　　处：《肿瘤》2013年第5期473-477,共5页Tumor

基　　金：国家自然科学基金资助项目(编号:81260501);云南省应用基础研究项目(编号:KKSA201126061)

摘　　要：合成致死(synthetic lethality,SL)是指两个非致死的非等位基因同时突变导致细胞死亡的现象,目前已经成为抗肿瘤药物研究的一个新方向。DNA修复缺陷可导致肿瘤发生,因此靶向修复缺陷基因可极大提高肿瘤的治疗效果。现已证实,聚腺苷二磷酸核糖聚合酶[poly(ADP-ribose)polymerase,PARP)]抑制剂靶向PARP基因抑制PARP蛋白的表达,从而抑制了DNA单链断裂修复,即能与突变的乳腺癌易感基因(breast cancer susceptibility gene,BRCA)或第10号染色体同源丢失性磷酸酶基因和张力蛋白基因(gene of phosphate and tension homology deleted on chromsome ten,PTEN)联合引起肿瘤细胞合成致死;在DNA错配修复(mismatch repair,MMR)系统缺陷的肿瘤细胞中,抑制DNA聚合酶β(DNA polymeraseβ,DNA polβ)与mutS蛋白同系物2(mut Shomolog 2,MSH2)基因缺失也可互为合成致死;抑制DNA聚合酶γ(DNA polymeraseγ,DNA polγ)与mutL同系物1(mutL homologue1,MLH1)基因缺失可导致合成致死,PTEN诱导的激酶l(PTEN-induced kinase1,PINK1)能与MSH2、MLH1或者MSH6基因缺失的肿瘤互为合成致死,因此PINK1可能是MMR缺陷型肿瘤的治疗靶点。本文旨在对与DNA修复缺陷相关的合成致死作一综述。The concept of synthetic lethality is defined as a genetic interaction of two non-allelic and non-lethal genes that when mutated simultaneously results in cell death, which has been proposed as a potential way to develop novel antitumor approaches. A new therapeutic approach targeting DNA repair defective genes may remarkably promote the antitumor efficacy based on the mechanism of tumorigenesis induced by DNA repair defects. Previous studies have demontrated that BRCA1 （breast cancer susceptibility gene 1）/BRCA2 or PTEN （phosphatase and tensin homolog deleted on chromosome 1 0） gene mutation with PARP [poly（ADP-ribose） polymerase] inhibitors could lead to killing effect in cancer cells; deletion of MSH2 （mutS homolog 2） gene with inhibiton of proofreading activity of DNA pol~ （polymerase 13） and the deletion ofMLH1 （mutL homolog 1） gene with inhibiton of proofreading activity of DNA pol could boyth lead to killing effect in cancer cells with MMR （mismatch repair） deficiency. PINK1 （PTEN-induced putative kinase 1） may be a potential therapeutic target for the treatment of MMR-deficient cancers with deletion of MSH2, MLH1 or MSH6 gene based on the theory of synthetic lethality. This review descibes the synthetic lethality associated with DNA repair defects.

关 键 词：肿瘤 DNA错配修复 聚腺苷二磷酸核糖聚合酶 PARP抑制剂 合成致死 

分 类 号：R73-361[医药卫生—肿瘤]