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. 2011 May;3(5):509-14.
doi: 10.18632/aging.100324.

Cockayne syndrome B protein antagonizes OGG1 in modulating CAG repeat length in vivo

Irina V Kovtun  1 , Kurt O Johnson, Cynthia T McMurray
Affiliations

Cockayne syndrome B protein antagonizes OGG1 in modulating CAG repeat length in vivo

Irina V Kovtun et al. Aging (Albany NY). 2011 May.

Abstract

OGG1 and MSH2/MSH3 promote CAG repeat expansion at Huntington's disease (HD) locusin vivo during removal of oxidized bases from DNA. CSB, a transcription-coupled repair (TCR) protein, facilitates repair of some of the same oxidative lesions. In vitro, a knock down CSB results in a reduction of transcription-induced deletions at CAG repeat tract. To test the role of CSB in vivo, we measured intergenerational and somatic expansion of CAG tracts in HD mice lacking CSB, OGG1, or both. We provide evidence that CSB protects CAG repeats from expansion by either active reduction of the tract length during parent-child transmission, or by antagonizing the action of OGG1, which tends to promote expansion in somatic cells. These results raise a possibility that actions of transcription-coupled and base excision repair pathways lead to different outcomes at CAG tracts in vivo.

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Conflict of interest statement

The authors of this manuscript have no conflict of interest to declare.

Figures

Figure 1.
Figure 1.. Intergenerational instability in HD mice deficient in different DNA repair enzymes.
Bars represent the percentage of progeny that display no change (stable), expansion or deletion of the CAG repeats in mice that harbor the human HD transgene in R6/1 (R), n=8 (white); R6/1(−/+)/Ogg1(−/−) (O), n=8 (light grey), R6/1D(−/+)/Msh2(−/−) (M), n=12 (dark grey) and R6/1(−/+)/CSB(−/−) (C), n=10 (black). Genescan analysis was performed on tail DNA at 3 weeks of age. Repeat length changes ranged from −4 to +4. The asterisk indicates statistically significant differences in expansions and deletions as judged by Student's t-test (P<0.05).
Figure 2.
Figure 2.. Somatic instability in HD mice deficient in different DNA repair enzymes.
(A) Age-dependent somatic expansion in selected tissues of R6/1, R6/1(−/+)/CSB(−/−), R6/1(−/+)/OGG1(−/−), R6/1(−/+)/CSB(−/−)/OGG1(−/−) presented as the mean length change of CAG repeats and SD. Ages and tissues are indicated. The asterisks indicate statistically significant differences as judged by Student's t-test; P<0.01 for (*), (**) and (***). (B) CAG repeat distributions in somatic tissues of control R6/1 and CSB knock out mice. t1 is repeat distribution in tail at 3 weeks; while expansion at 39-42 weeks in shown in tail (t2), brain (br) and liver (lv). Vertical dashed line designates the major CAG length in the distributions measured in tail DNA at 3 weeks of age.
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