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mismatch repair gene

肾内泌尿

关键词肾内泌尿 临床研究术语 错配修复基因

词汇介绍

拓展阅读

解析

Mismatch  英  /ˌmɪsˈmætʃ/  美  /ˌmɪsˈmætʃ/

释    义   v. 使配错;使不适当地在一起;

               n. 错配,搭配不当;不匹配,不协调;实力悬殊(或不公平)的比赛

例    句   Our minds are not modern, and many of our woes have to do with this mismatch between our Stone-age psychologies and the world in which we now live.我们的思想并不现代,事实上,生活中的许多不幸都与我们旧石器时代的心理特征以及当下生活世界之间的不相匹配有关。

 

Repair  英  /rɪˈpeə(r)/  美  /rɪˈper/

释    义   v. 修理;修复,补救;(使)重归于好;(结伴)去;

               n. 修理;修补过的部位;具体情况,物质条件;常去;常去的场所

例    句   We clean and repair the machines as a matter of routine.我们定期清洗和修理机器。

概述

  mismatch repair即错配修复,简写为MMR。错配修复(MMR)基因是生物进化过程中的保守基因,属于看家基因,具有修复DNA碱基错配,有利于DNA复制高保真性,有利于维持基因组的稳定性和降低自发性突变等。成员有hMLH-1、hMSH-2、hPMS-1和hPMS-2蛋白,其中hMLH-1和hMSH-2蛋白是MMR家族中的主要成员。它的表达缺失可引起DNA复制过程中错配的累积,导致微卫星不稳定(MSI)的发生,约15%的结直肠癌是经由MSI途径引发的。

Inactivation of DNA Repair Triggers Neoantigen Generation and Impairs Tumour Growth复制标题

DNA修复失活触发新抗原生成并损害肿瘤生长

发表时间:2017-12-07

影响因子:42.8

作者: Germano G

期刊:Nature

Molecular alterations in genes involved in DNA mismatch repair (MMR) promote cancer initiation and foster tumour progression. Cancers deficient in MMR frequently show favourable prognosis and indolent progression. The functional basis of the clinical outcome of patients with tumours that are deficient in MMR is not clear. Here we genetically inactivate MutL homologue 1 (MLH1) in colorectal, breast and pancreatic mouse cancer cells. The growth of MMR-deficient cells was comparable to their proficient counterparts in vitro and on transplantation in immunocompromised mice. By contrast, MMR-deficient cancer cells grew poorly when transplanted in syngeneic mice. The inactivation of MMR increased the mutational burden and led to dynamic mutational profiles, which resulted in the persistent renewal of neoantigens in vitro and in vivo, whereas MMR-proficient cells exhibited stable mutational load and neoantigen profiles over time. Immune surveillance improved when cancer cells, in which MLH1 had been inactivated, accumulated neoantigens for several generations. When restricted to a clonal population, the dynamic generation of neoantigens driven by MMR further increased immune surveillance. Inactivation of MMR, driven by acquired resistance to the clinical agent temozolomide, increased mutational load, promoted continuous renewal of neoantigens in human colorectal cancers and triggered immune surveillance in mouse models.

译文

DNA错配修复(MMR)中涉及的基因的分子变化可促进癌症的发生并促进肿瘤的进展。缺乏MMR的癌症通常显示出良好的预后和缓慢的进展。 MMR不足的肿瘤患者的临床结果的功能基础尚不清楚。在这里,我们在大肠,乳腺癌和胰腺小鼠癌细胞中使MutL同源物1(MLH1)遗传失活。 MMR缺陷细胞的体外生长和免疫受损小鼠移植后的生长情况与其熟练的同类细胞相当。相比之下,MMR缺陷型癌细胞移植到同系小鼠中后生长不良。 MMR的失活增加了突变负担并导致了动态突变图谱,从而导致了新抗原在体外和体内的持续更新,而MMR熟练的细胞随着时间的推移表现出稳定的突变量和新抗原图谱。当已将MLH1灭活的癌细胞积聚了几代新抗原时,免疫监测得到改善。当仅限于克隆人群时,MMR驱动的新抗原的动态产生进一步增强了免疫监视。 MMR的失活是由对临床药物替莫唑胺的获得性耐药性驱动的,突变负荷增加,促进人结肠直肠癌中新抗原的持续更新,并引发了小鼠模型的免疫监视。