Abstract
RAD6 participates in DNA double-strand breaks (DSBs) repair by ubiquitinating histone H2B in mitotic cells. In terminally differentiated cells, however, the mechanisms of DNA damage repair are less well known. In this study, we investigate whether RAD6B is involved in DSBs repair in neurons and effects of RAD6B deficiency on neuronal survival. We compared neurons of RAD6B-deficient mice with those of littermate wild type (WT) mice and induced DNA damage by X-ray irradiation. We provide evidence that RAD6B is essential for neural DDR and RAD6B deficiency results in increased genomic instability and neurodegeneration. Moreover, higher levels of p53 and p21 are present in the brains of RAD6B-deficient mice, which may be responsible for neuronal senescence, and degeneration. In addition, behavioral experiments show that RAD6B-deficient mice exhibit marked learning and memory deficits. In conclusion, these findings suggest that RAD6B is critical for neural integrity and that the absence of RAD6B accelerates neurodegeneration in mice.
Highlights
Biological cells are affected by various genotoxic stressors from endogenous and exogenous sources, and it is estimated that a typical mammalian cell undergoes ∼2 × 105 lesions per day (Harper and Elledge, 2007; Ouyang et al, 2015; White and Vijg, 2016; Hegde et al, 2017)
To compare the repair processes for double-strand breaks (DSBs) in the neurons of RAD6B-deficient mice with those in the neurons of wild type (WT) mice, we observed the formation of ionizing radiation-induced nuclear foci (IRIF) at the broken sites after inducing damage by X-ray irradiation. γ-H2AX foci were used as a marker of DNA damage, while MDC1, 53BP1, RNF8, and BRCA1 were co-stained with γ-H2AX as repair factors
Most of them colocalized with the corresponding γ-H2AX foci, indicating that they were recruited to the broken sites after X-ray irradiation
Summary
Biological cells are affected by various genotoxic stressors from endogenous and exogenous sources, and it is estimated that a typical mammalian cell undergoes ∼2 × 105 lesions per day (Harper and Elledge, 2007; Ouyang et al, 2015; White and Vijg, 2016; Hegde et al, 2017). DNA DSBs are the most harmful to cells (Jackson and Bartek, 2009; Ouyang et al, 2015), which often lead to chromosomal rearrangements, senescence, tumorigenesis, or cell death (Lee and Mckinnon, 2007; White and Vijg, 2016). To avert those potentially devastating consequences, cells initiate highly evolved DNA damage response (DDR), and detect and repair damaged DNA. Based on different factors, including the cell type, cell-cycle stage and the severity of the damage, accurate repair leads to restoration of an intact double helix, while failed repair often cause apoptosis, and senescence or even tumor formation (Barzilai, 2010)
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