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

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          Abstract

          OGG1 and MSH2/MSH3 promote CAG repeat expansion at Huntington's disease (HD) locus in 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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          Most cited references38

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          Repeat instability: mechanisms of dynamic mutations.

          Disease-causing repeat instability is an important and unique form of mutation that is linked to more than 40 neurological, neurodegenerative and neuromuscular disorders. DNA repeat expansion mutations are dynamic and ongoing within tissues and across generations. The patterns of inherited and tissue-specific instability are determined by both gene-specific cis-elements and trans-acting DNA metabolic proteins. Repeat instability probably involves the formation of unusual DNA structures during DNA replication, repair and recombination. Experimental advances towards explaining the mechanisms of repeat instability have broadened our understanding of this mutational process. They have revealed surprising ways in which metabolic pathways can drive or protect from repeat instability.
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            Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage.

            DNA damage generated by oxidant byproducts of cellular metabolism has been proposed as a key factor in cancer and aging. Oxygen free radicals cause predominantly base damage in DNA, and the most frequent mutagenic base lesion is 7,8-dihydro-8-oxoguanine (8-oxoG). This altered base can pair with A as well as C residues, leading to a greatly increased frequency of spontaneous G.C-->T.A transversion mutations in repair-deficient bacterial and yeast cells. Eukaryotic cells use a specific DNA glycosylase, the product of the OGG1 gene, to excise 8-oxoG from DNA. To assess the role of the mammalian enzyme in repair of DNA damage and prevention of carcinogenesis, we have generated homozygous ogg1(-/-) null mice. These animals are viable but accumulate abnormal levels of 8-oxoG in their genomes. Despite this increase in potentially miscoding DNA lesions, OGG1-deficient mice exhibit only a moderately, but significantly, elevated spontaneous mutation rate in nonproliferative tissues, do not develop malignancies, and show no marked pathological changes. Extracts of ogg1 null mouse tissues cannot excise the damaged base, but there is significant slow removal in vivo from proliferating cells. These findings suggest that in the absence of the DNA glycosylase, and in apparent contrast to bacterial and yeast cells, an alternative repair pathway functions to minimize the effects of an increased load of 8-oxoG in the genome and maintain a low endogenous mutation frequency.
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              OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells.

              Although oxidative damage has long been associated with ageing and neurological disease, mechanistic connections of oxidation to these phenotypes have remained elusive. Here we show that the age-dependent somatic mutation associated with Huntington's disease occurs in the process of removing oxidized base lesions, and is remarkably dependent on a single base excision repair enzyme, 7,8-dihydro-8-oxoguanine-DNA glycosylase (OGG1). Both in vivo and in vitro results support a 'toxic oxidation' model in which OGG1 initiates an escalating oxidation-excision cycle that leads to progressive age-dependent expansion. Age-dependent CAG expansion provides a direct molecular link between oxidative damage and toxicity in post-mitotic neurons through a DNA damage response, and error-prone repair of single-strand breaks.
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                Author and article information

                Journal
                Aging (Albany NY)
                ImpactJ
                Aging (Albany NY)
                Impact Journals LLC
                1945-4589
                May 2011
                3 May 2011
                : 3
                : 5
                : 509-514
                Affiliations
                1 Department of Pharmacology and Experimental Therapeutics, Mayo Clinic and Foundation, Rochester, MN 55905, USA
                2 Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
                Author notes
                Corresponding authors: Irina V. Kovtun, PhD; Cynthia T. McMurray, PhD; kovtun.irina@ 123456mayo.edu ; CTMcMurray@ 123456lbl.gov
                Article
                3156601
                21566259
                b2e7dc66-df60-47e0-93d5-1d1d6b65dd13
                Copyright: © 2011 Kovtun et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                Categories
                Research Paper

                Cell biology
                transcription coupled repair,csb,huntington's disease,cag expansion,base excision dna repair

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