Drummond J T
Department of Biology, Indiana University, Bloomington 47405, USA.
Adv Enzyme Regul. 1999;39:129-41. doi: 10.1016/s0065-2571(98)00013-2.
Mismatch recognition in human cells is mediated by two heterodimers, MutS alpha and MutS beta. MutS alpha appears to shoulder primary responsibility for mismatch correction during replication, based on its relative abundance and ability to recognize a broad spectrum of base-base and base-insertion mismatches. Because MutS alpha and MutS beta share a common component, MSH2, conditions that influence the expression or degradation of MSH3 or MSH6 can redistribute the profile of mismatch recognition and repair. MSH3 is linked by a shared promoter with DHFR, connecting two pathways with key roles in DNA metabolism. In a classic example of gene amplification, the DHFR (and MSH3) locus can become amplified to several hundred copies in the presence of methotrexate. Under these conditions, MutS beta forms at the expense of MutS alpha, and the mutation rate in these tumor cells rises more than 100-fold. The implications for cancer chemotherapy include a potential increase in mutability when tumors are treated with methotrexate, which could increase the frequency of subsequent mutations that influence the tumor's drug sensitivity or aggressiveness. Because processing certain types of DNA damage by the mismatch repair pathway has also been implicated in tumor sensitivity to agents such as cisplatin, changes in expression at the DHFR/MSH3 locus may have further relevance to the outcome of multi-drug treatment regimens.
人类细胞中的错配识别由两个异源二聚体MutSα和MutSβ介导。基于其相对丰度和识别广泛碱基-碱基和碱基插入错配的能力，MutSα似乎在复制过程中对错配校正承担主要责任。由于MutSα和MutSβ共享一个共同组分MSH2，影响MSH3或MSH6表达或降解的条件可重新分配错配识别和修复的情况。MSH3通过一个共享启动子与二氢叶酸还原酶（DHFR）相连，从而连接了在DNA代谢中起关键作用的两条途径。在一个典型的基因扩增例子中，在甲氨蝶呤存在的情况下，DHFR（和MSH3）基因座可扩增至数百个拷贝。在这些条件下，MutSβ形成而MutSα减少，并且这些肿瘤细胞中的突变率上升超过100倍。对癌症化疗的影响包括用甲氨蝶呤治疗肿瘤时变异性可能增加，这可能会增加随后影响肿瘤药物敏感性或侵袭性的突变频率。由于错配修复途径处理某些类型的DNA损伤也与肿瘤对顺铂等药物的敏感性有关，DHFR/MSH3基因座表达的变化可能与多药治疗方案的结果有进一步的相关性。
