Triplet repeat sequences, such as CAG/CTG, expand in the genome to cause several neurological disorders. Interestingly, the oxidatively damaged nucleobase 8-oxo-7,8-dihydroguanine (8-oxoG) has been implicated in triplet repeat expansion. Our overall objective is to define the molecular mechanism of CAG/CTG triplet repeat expansion and determine the extent to which 8-oxoG plays a role as the chemical founder event. We have identified a hot spot for DNA damage in the non-canonical structures adopted by CAG/CTG DNA, and performed a comprehensive kinetic analysis of base excision repair (BER) on these repetitive DNA substrates. These results have allowed us to propose a toxic cycle in which BER is initiated on triplet repeat sequences and damage accumulates in repair intermediates, resulting in an incremental expansion of the triplet repeat sequence.

Roles of DNA damage, repair, and structure in triplet repeat expansion

245th National Meeting (2013)

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