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Organic Chemistry Seminar

Wednesday, February 22, 2012
4:00pm to 5:00pm
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Noyes 153 (J. Holmes Sturdivant Lecture Hall)
Roles of DNA Damage, Repair, and Structure in Triplet Repeat Expansion
Sarah Delaney, professor of chemistry, Brown University,
Triplet repeat sequences, such as CAG/CTG, expand in the human genome to cause several neurological disorders. This repetitive DNA sequence is known to adopt non-canonical structures such as stem-loop hairpins. Furthermore, work from other laboratories has implicated the DNA repair enzyme 8-oxo-7,8-dihydroguanine glycosylase (OGG1) in triplet repeat expansion. OGG1 initiates the base excision repair (BER) process in mammalian cells by excising the oxidatively damaged nucleobase 8-oxo-7,8-dihydroguanine (8-oxoG) from DNA. Motivated by the demonstrated involvement of 8-oxoG and OGG1 in triplet repeat expansion we first examined the susceptibility of CAG/CTG DNA to oxidative damage. We identified a hot spot for oxidative damage in the stem-loop hairpin formed by triplet repeat DNA. We next conducted a comprehensive kinetic analysis of OGG1 activity. We demonstrated that changes to the sequence composition are well tolerated whereas the structure of the DNA substrate modulates OGG1 activity. Indeed, duplexes containing 8-oxoG are efficiently repaired, whereas the stem-loop hairpin is not repaired and 8-oxoG accumulates in this non-canonical structure. Taken together, these results have allowed us to propose a toxic cycle in which BER is initiated on triplet repeat duplexes, and accumulation of damage in a stem-loop hairpin intermediate initiates a toxic cycle of damage and misrepair that result in an incremental expansion of the triplet repeat sequence. I will also describe experiments in which the triplet repeat sequence was examined in the context of a nucleosome and how these data influence our understanding of how the repetitive sequence packages in chromatin.
For more information, please contact Arleen (Lynne) Martinez by phone at 4004 or by email at [email protected].