title: Bcl2 impedes DNA mismatch repair by directly regulating the hMSH2-hMSH6 heterodimeric complex.
abstract: Bcl2 has been reported to suppress DNA mismatch repair (MMR) with promotion of mutagenesis, but the mechanism(s) is not fully understood. MutSalpha is the hMSH2-hMSH6 heterodimer that primarily functions to correct mutations that escape the proofreading activity of DNA polymerase. Here we have discovered that Bcl2 potently suppresses MMR in association with decreased MutSalpha activity and increased mutagenesis. Exposure of cells to nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone results in accumulation of Bcl2 in the nucleus, which interacts with hMSH6 but not hMSH2 via its BH4 domain. Deletion of the BH4 domain from Bcl2 abrogates the ability of Bcl2 to interact with hMSH6 and is associated with enhanced MMR efficiency and decreased mutation frequency. Overexpression of Bcl2 reduces formation of the hMSH2-hMSH6 complex in cells, and purified Bcl2 protein directly disrupts the hMSH2-hMSH6 complex and suppresses MMR in vitro. Importantly, depletion of endogenous Bcl2 by RNA interference enhances formation of the hMSH2-hMSH6 complex in association with increased MMR and decreased mutagenesis. Thus, Bcl2 suppression of MMR may occur in a novel mechanism by directly regulating the heterodimeric hMSH2-hMSH6 complex, which potentially contributes to genetic instability and carcinogenesis.
authors.affiliation: Department of Medicine, Shands Cancer Center, University of Florida, Gainesville, Florida 32610-3633, USA.
authors.forename: Yongzhong
authors.initials: Y
authors.lastname: Hou
authors.forename: Fengqin
authors.initials: F
authors.lastname: Gao
authors.forename: Qinhong
authors.initials: Q
authors.lastname: Wang
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Zhao
authors.forename: Tammy
authors.initials: T
authors.lastname: Flagg
authors.forename: Yangde
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xingming
authors.initials: X
authors.lastname: Deng
mesh_terms: D020137:Base Pair Mismatch; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019281:Dimerization; D017353:Gene Deletion; D020868:Gene Silencing; D006801:Humans; D051718:MutS Homolog 2 Protein / Q000378:metabolism*; D009154:Mutation; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D034622:RNA Interference; D013347:Subcellular Fractions
chemical_list: D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D019253:Proto-Oncogene Proteins c-bcl-2; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein