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Abstract DNA mismatch repair (MMR) maintains replication fidelity by correcting mispaired nucleotides incorporated by DNA polymerases. Defects in MMR lead to cancers characterized by microsatellite instability. Recently, chromatin mechanisms that regulate MMR have been discovered, which sheds new light on MMR deficiency and its role in tumorigenesis. This review summarizes these chromatin-level mechanisms that regulate MMR and their implications for tumor development.