Cellular and Molecular bases of DNA damage response in neurons and its links to neurodegeneration
Miguel Angel Lafarga
Department of Anatomy and Cell Biology at University of Cantabria
Neurons are highly vulnerable to DNA damage induced by transcriptional activity and genotoxic agents such as ROS, ionizing radiation (IR) and chemotherapeutic drugs. Although neurons activate robust DNA repair mechanisms, there is growing evidence that defective DNA repair with accumulation of DNA lesions and loss of genome integrity underlies aging and many neurodegenerative disorders. Following IR-induced DNA double strand breaks, neurons accumulate unrepaired DNA within persistent DNA damage foci (PDDF) of chromatin. Such PDDF are featured by hyper-relaxation of chromatin, permanent activation of DNA damage/repair signaling (gH2AX, 53BP1), lack of transcription and localization in repressive nuclear microenvironments. By confining damaged DNA, PDDF would help preserving genomic integrity and preventing the production of aberrant proteins encoded by damaged genes. ChIP-seq analysis of genome-wide gH2AX distribution, a DNA damage marker, revealed a number of genomic regions enriched in gH2AX signal in IR-treated cerebral cortical neurons. Some of these regions are in close proximity to genes encoding essential proteins for neuronal functions and human neurodegenerative disorders, suggesting that these regions are more vulnerable to DNA damage or more refractory to DNA repair and may potentially be involved in neurodegenerative disorders.
Host: Jorge Valero