1. OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells (Irina V. Kovtun et al., Nature, 2007) Yizhang Chen 10/18/2012 Student Presentation

2. Background Huntington’s disease Progressive neurodegenerative disorders. Caused by CAG expansion in the coding region of the Huntington’s disease gene (HD). – CAG expansion – HD gene express increasingly – Accumulation of toxic HD protein – Accelerated cell death How CAG expansions occur in post-mitotic neurons?

3. Whether CAG expansion correlates with DNA oxidation ？ The level and accumulation of oxidative DNA damage correlated well with expansion. Age-dependent accumulation restricted to oxidative lesions. Oxidative damage accumulation due to the aging process.

4. Measure the repair activity The accumulation of oxidative lesions is not due to a loss of repair.

5. CAG expansion present in the terminally differentiated neurons. In vitro, base oxidation directly lead to CAG expansion (data not shown). Peroxide led to CAG expansion of medium-length and disease-length alleles. Comet Assay CAG expansion occurred in the process of repairing SSB. Only CAG repeats at long HD locus expanded in vitro (data not shown). Whether expansion occurs during normal repair of SSB?

6. Whether DNA glycosylases contributed to CAG expansion? Loss of OGG1 suppressed or delayed age-dependent expansion in vivo. OGG1 may be the only dominant factor.

7. Somatic expansion in R6/1 animals recapitulated the features that in human Length-dependent Sequence-dependent Occurred at other repetitive sequences Loss of OGG1 altered properties

8. Regenerate CAG expansion during BER reconstituted in vitro Add OGG1, APE1 and polymerase β step by step Expansion initiates through strand displacement/slippage during the gap-filling step of BER.

9. Conclusions In vivo, age-dependent somatic CAG expansion initiates from an OGG1-mdiated BER mechanism. ‘Toxic oxidation cycle’ model