Regulation of Transcription Patterns, Poly-Adp-ribose, and RNA-DNA Hybrids by the ATM Protein Kinase

The ataxia telangiectasia mutated (ATM) protein kinase is a master regulator of the DNA damage response and also an important sensor of oxidative stress. Analysis of gene expression in ataxia-telangiectasia (A -T) patient brain tissue shows that large-scale transcriptional changes occur in patient cerebellum that correlate with the expression level and guanine -cytosine (GC) content of transcribed genes. In human neuron -like cells in culture, we map locations of poly(ADP-ribose) and RNA -DNA hybrid accumulation genome-wide with ATM inhibition and find that these marks also coincide with high transcription levels, active transcription histone marks, and high GC content. Antioxidant treatment reverses the accumulation of R -loops in transcribed regions, consistent with the central role of reactive oxygen species in promoting these lesions. Based on these results, we postulate that transcription -associated lesions accumulate in ATM -deficient cells and that the single -strand breaks and PARylation at these sites ultimately generate changes in transcription that compromise cerebellum function and lead to neurodegeneration over time in A -T patients.