Coupling distant sites in DNA during DNA mismatch repair

Human MSH2 (hMSH2) Protein Controls ATP Processing by hMSH2-hMSH6

“…Subsequent ATP binding by hMSH2-hMSH6 produces a sliding clamp (8,30). Several models have been proposed for MMR (16). Our studies detail the kinetic steps associated with ADP/ATP processing by the individual subunits of human hMSH2-hMSH6 (Fig.…”

“…ADP 3 ATP exchange is rate-limiting and provokes a conformational transition that results in the formation of a sliding clamp, which dissociates from the mismatch (8,11). One possible model for MMR suggests that mismatch-dependent loading of multiple hydrolysis-independent sliding clamps activates downstream MMR components (8,(12)(13)(14), whereas another model suggests hydrolysis-dependent translocation to contact downstream MMR components (15)(16)(17). The management of ATP processing by the two MSH subunits is predicted to be significantly different for these two models.…”

DNA mismatch repair: Molecular mechanism, cancer, and ageing

“…However, physical barriers separating a mispair from a 5′ strand break did not seem to inhibit MMR in human cell extracts (Wang and Hays, 2004). These differences may be attributable to multiple pathways or possibly more than one distinct "activation" step (see discussion in Kolodner et al, 2007;Wang and Hays, 2007). A definitive experiment is hard to come by in this system, but the weigh of the evidence thus far argues for some type of cis model in which information is communicated along the DNA helix.…”

“…Any proposed model must explain how information is propagated from the mismatch site to the excision start site located some distance away, and this has led to two general classes of models in which MutS and MutL and their homologues communicate with downstream players in cis or in trans (see recent discussions in Kolodner et al, 2007;Kunkel and Erie, 2005;Modrich, 2006). In a trans activation model, communication occurs between MutS-MutL complexes at a mismatch and proteins that operate downstream like MutH by protein-protein interactions accompanied by DNA bending.…”

“…a strand break possibly in the context of other auxiliary proteins such as PCNA and/ or RFC in eukaryotic cells at which time they activate the excision step and/or the endonuclease activity of MutLα (see Iyer et al, 2006;Kolodner et al, 2007).…”