Mispair-bound human MutS–MutL complex triggers DNA incisions and activates mismatch repair  

作　　者：Janice Ortega Grace Sanghee Lee Liya Gu Wei Yang Guo-Min Li 

机构地区：[1]Department of Radiation Oncology,University of Texas Southwestern Medical Center,Dallas,TX,USA [2]Department of Toxicology and Cancer Biology,University of Kentucky College of Medicine,Lexington,KY,USA [3]Laboratory of Molecular Biology,National Institute of Diabetes and Digestive and Kidney Diseases,National Institutes of Health,Bethesda,MD,USA [4]Present address:Division of Viral Hepatitis,National Center for HIV/AIDS,Viral Hepatitis,STD and TB Prevention,Centers for Disease Control and Prevention,Atlanta,GA,USA

出　　处：《Cell Research》2021年第5期542-553,共12页细胞研究（英文版）

基　　金：This work was supported in part by grants from the Cancer Prevention&Research Institute of Texas(RR160101);the National Institutes of Health(R01 GM112702);the Magnolia Council of Tower Cancer Research Foundation(to G.M.L.);NIH intramural research grant(DK036119,to W.Y.)。

摘　　要：DNA mismatch repair(MMR)relies on MutS and MutL ATPases for mismatch recognition and strand-specific nuclease recruitment to remove mispaired bases in daughter strands.However,whether the MutS–MutL complex coordinates MMR by ATP-dependent sliding on DNA or protein–protein interactions between the mismatch and strand discrimination signal is ambiguous.Using functional MMR assays and systems preventing proteins from sliding,we show that sliding of human MutSαis required not for MMR initiation,but for final mismatch removal.MutSαrecruits MutLαto form a mismatch-bound complex,which initiates MMR by nicking the daughter strand 5′to the mismatch.Exonuclease 1(Exo1)is then recruited to the nick and conducts 5′→3′excision.ATP-dependent MutSαdissociation from the mismatch is necessary for Exo1 to remove the mispaired base when the excision reaches the mismatch.Therefore,our study has resolved a long-standing puzzle,and provided new insights into the mechanism of MMR initiation and mispair removal.

关 键 词：REMOVE DAUGHTER mismatch 

分 类 号：Q2[生物学—细胞生物学]