DNA Damage and Repair and Epigenetic Modification in the Role of Oxoguanine Glycosylase 1 in Brain Development

Abstract

Oxoguanine glycosylase 1 (OGG1) repairs the predominant reactive oxygen species (ROS)-initiated DNA lesion 8-oxoguanine (8-oxoG). Human OGG1 polymorphisms resulting in reduced DNA repair associate with an increased risk for disorders like cancer and diabetes, but the role of OGG1 in brain development is unclear. Herein, we show that Ogg1 knockout mice at 2-3 months of age exhibit enhanced gene- and sex-dependent DNA damage (strand breaks) and decreased epigenetic DNA methylation marks (5-methylcytosine, 5-hydroxymethylcytosine), both of which were associated with increased cerebellar calbindin levels, reduced hippocampal postsynaptic function, altered body weight with age and disorders of brain function reflected in behavioural tests for goal-directed repetitive behaviour, anxiety and fear, object recognition and spatial memory, motor coordination and startle response. These results suggest that OGG1 plays an important role in normal brain development, possibly via both its DNA repair activity and its role as an epigenetic modifier, with OGG1 deficiencies potentially contributing to neurodevelopmental disorders.

BRCA1 protein dose-dependent risk for embryonic oxidative DNA damage, embryopathies and neurodevelopmental disorders with and without ethanol exposure

“…Previous studies of ROS-mediated developmental disorders have consistently shown that models deficient in proteins involved in DNA damage recognition and repair signaling [ 37 , 38 ], DNA repair [ 13 , 15 , 30 , 39 ] or antioxidative activity [ 22 , 35 ] were more susceptible to developmental disorders caused by several different ROS-initiating teratogens, and in some cases even caused by physiological levels of ROS formation in untreated animals [ 14 , 30 , [34] , [35] , [36] , 40 , 41 ]. This study's findings align with these previous observations, as Brca1 direct KO +/- embryos exhibit enhanced γH2AX following both saline and EtOH exposures, with the latter showing an additive effect.…”

Altered Epigenetic Marks and Gene Expression in Fetal Brain, and Postnatal Behavioural Disorders, Following Prenatal Exposure of Ogg1 Knockout Mice to Saline or Ethanol

“…ESR1 inhibition is important in the formation of long-term memory in the mouse hippocampus [ 48 ], and a role for OGG1 in repressing ESR1 to modulate learning and memory formation has been postulated because hippocampal regions of Ogg1 KO mice exhibited upregulation of Esr1 target genes [ 17 ]. We previously saw OGG1- and sex-dependent enhanced DNA strand breaks, decreased DNA methylation levels and behaviour deficits including alterations in spatial and recognition memory in untreated OGG1-deficient young mice (~2–3 months) [ 10 ]. The presence of sex-dependent differences in young OGG1-deficient mice suggests that estrogen may play an important role in regulating gene expression in an OGG1-dependent manner, particularly during development, so Esr1 and Esr2 mRNA levels and protein levels were quantified in fetal brains.…”

“…However a decreased performance in an open field box test (measured via number of crossed lines, number of rears, mean speed and time immobile) was observed in aging (26 months) Ogg1 − / − mice (sexes combined and tested at 20 lux) [ 50 ]. Our own data using 3-month-old untreated OGG1-deficient mice showed no differences in open field activity except for a trend for increased time spent in the centre zone by Ogg1 −/− females when tested at ~50 lux [ 10 ].…”

“…Aside from the role of OGG1 in DNA repair, recent studies have revealed multiple epigenetic and other non-mutational mechanisms by which 8-oxoG and OGG1 may regulate gene transcription and signal transduction [ 8 , 9 ]. We recently found that untreated OGG1-deficient progeny exhibit a sex-dependent enhancement in DNA strand breaks, decreased DNA methylation levels and disorders of brain function compared to Ogg1 +/+ littermates [ 10 ].…”

Exploring the epigenetic landscape: The role of 5-hydroxymethylcytosine in neurodevelopmental disorders

“…The absence of Ogg1 in the brain leads to various cellular and molecular events, including increased apoptosis and abnormal neuronal connectivity (Wong et al, 2008 ), key pathomorphological features of autism. In fact, Bhatia et al ( 2022 ) explored the involvement of OGG1, using OGG1 knockout mice, in brain development and its role in repairing DNA lesions induced by reactive oxygen species. Their findings demonstrate that young Ogg1 knockout mice displayed sex- and gene-specific DNA damage, reduced DNA methylation marks, elevated cerebellar calbindin levels, impaired hippocampal function, altered body weight and various behavioral abnormalities, highlighting the significance of OGG1 in normal brain development through its potential functions in DNA repair and epigenetic regulation, with implications for NDDs.…”