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Yizhang Chen 10/18/2012

Student Presentation. OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells (Irina V. Kovtun et al., Nature, 2007). Yizhang Chen 10/18/2012. Background. Huntington’s disease Progressive neurodegenerative disorders.

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Yizhang Chen 10/18/2012

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

  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. Whether expansion occurs during normal repair of SSB? • 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).

  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

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