OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells

Abstract

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.

Topoisomerase 1 and Single-Strand Break Repair Modulate Transcription-Induced CAG Repeat Contraction in Human Cells

“…Similarly, among those genes with little effect on CAG contraction in human cells (28), three have been tested in mouse models and shown to have little effect on CAG repeats, including MSH6 (52), XPC (8), and FEN1 (50,51). Interestingly, only in the case of the OGG1 glycosylase discussed below do the results differ, with deficiencies having no effect on CAG contraction in human cells (32), but large effects in mice (21). Overall, the otherwise good agreement between these two assays suggests that screening candidates in human cells will be a productive way to select genes to test in mice.…”

“…Thus, in the absence of OGG1, CAG repeats become more stable. Strikingly, mouse models of Huntington disease that are genetically deficient for OGG1 have much more stable CAG repeats in brain than do OGG1-positive mice (21). It is curious that the TOP1-TDP1-SSBR pathway acts to suppress CAG instability, while the OGG1-APE1-BER pathway acts to stimulate repeat instability.…”

“…It is responsible for excising 8-oxo-guanine, a common base damage caused by reactive oxygen species (53). In cell extracts and in mice, it has been shown that OGG1 normally acts to promote CAG repeat expansions (21,33). Thus, in the absence of OGG1, CAG repeats become more stable.…”

Microsatellite mutations in buccal cells are associated with aging and head and neck carcinoma

“…For example, the tetranucleotide marker MycL1 was found to be more stable than other microsatellites in MMR-negative cells, but more unstable in MMR-positive cells (Hatch and Farber, 2004). Kovtun et al (2007) demonstrated agedependent expansion of a human Huntington's disease-related trinucleotide in transgenic mice). The levels of expansion were greatly increased in double-transgenic mice that lacked a single base-excision repair enzyme, 7,8-dihydro-8-oxoguanine-DNA glycosylase (OGG1), indicating the important role of oxidative damage in the expansion process.…”

Neuroprotection for Huntington’s Disease: Ready, Set, Slow

“…61 Proximal events mediated by mutant huntingtin in turn trigger cascades of both damaging and compensatory molecular processes and genetic programs. These events and sequelae include mitochondrial dysfunction, energy depletion, [62][63][64] oxidative stress, 65,66 DNA damage, 67 synaptic stress, 68 disordered neurophysiology, 69 proapoptotic signals, 70 protein aggregation, [71][72][73] malfunctioning proteolysis, 74 autophagy, [75][76][77][78][79] ubiquitin/ proteosomal dysfunction, [80][81][82] neurotrophin deficiency, [83][84][85] and©disrupted©intracellular©transport 86 -all©of©which might© play© a© role© in© neuronal© death. 87© The© presence© of huntingtin© or© its© fragments© in© the© nucleus© seems© to© particularly© drive© pathology.…”