Albany 2015:Book of Abstracts
June 9-13 2015
©Adenine Press (2012)
The Road to Genome Expansion is Paved with Good Intentions: When DNA Repair goes Awry
Triplet repeat sequences, such as CAG/CTG, expand in the human 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 (Kovtun & McMurray, 2007). Our overall objective is to define the molecular mechanism of 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. In fact, rather than contributing to genetic stability, initiation of BER on triplet repeat DNA is detrimental and ultimately results in disease-initiating expansion. Recent work has explored BER on CAG/CTG sequences in the context of nucleosome core particles.
This research has been supported by NIH ES019296.
I. V. Kovtun, Y. Liu, M. Bjoras, A. Klungland, S. H. Wilson, and C. T. McMurray. (2007) Nature 447, 447-452.
Department of Chemistry