Mismatch Repair in Neurodegenerative Diseases

Trinucleotide repeat expansions cause more than 30 severe neuromuscular and neurodegenerative disorders, including Huntington’s disease, myotonic dystrophy type 1, and fragile X syndrome. Although the MMR system is well known for its role in maintaining replication fidelity, key MMR proteins, especially MutSβ, have been implicated in promoting trinucleotide repeat instability. However, the molecular basis by which the MMR system causes trinucleotide repeat expansions is not known.

Representative Publications

Williams G, Paschalis V, Ortega J, Li GM, Schwabe J, Lahue R (2020). HDAC3 deacetylates the DNA mismatch repair protein MutSβ to stimulate triplet repeat expansions. Proc Natl Acad Sci USA, 117 (38) 23597-23605

Chan, NL, Guo J, Zhang T, Mao G, Hou C, Yuan F, Huang J, Zhang Y, Wu J, Gu L, et al. (2013). Coordinated processing of 3' slipped (CAG)n/(CTG)n hairpins by DNA polymerases beta and delta preferentially induces repeat expansions. J Biol Chem 288, 15015-15022.

Guo J, Gu L, Leffak M, Li GM (2016). MutSbeta promotes trinucleotide repeat expansion by recruiting DNA polymerase beta to nascent (CAG)n or (CTG)n hairpins for error-prone DNA synthesis. Cell Res 26, 775-786.

Hou C, Chan NL, Gu L, Li GM (2009). Incision-dependent and error-free repair of (CAG)(n)/(CTG)(n) hairpins in human cell extracts. Nat Struct Mol Biol 16, 869-875.

Zhang T, Huang J, Gu L, Li GM (2012). In vitro repair of DNA hairpins containing various numbers of CAG/CTG trinucleotide repeats. DNA Repair 11, 201-209.