RAD52 is required for RNA-templated recombination repair in post-mitotic neurons

• Published in: The Journal of biological chemistry 2018-01, Vol.293 (4), p.1353-1362
• Main Authors: Welty, Starr, Teng, Yaqun, Liang, Zhuobin, Zhao, Weixing, Sanders, Laurie H., Greenamyre, J. Timothy, Rubio, Maria Eulalia, Thathiah, Amantha, Kodali, Ravindra, Wetzel, Ronald, Levine, Arthur S., Lan, Li
• Format: Article
• Language: English
• Subjects: Alzheimer’s disease; amyloid β (Aβ); Animals; Cell Biology; DNA Breaks, Double-Stranded; G1 Phase - physiology; Mitosis - physiology; neuron; Neurons - cytology; Neurons - metabolism; oxidative damage; Rad52 DNA Repair and Recombination Protein - genetics; Rad52 DNA Repair and Recombination Protein - metabolism; Rats; recombination; Recombination, Genetic - physiology; Resting Phase, Cell Cycle - physiology; RNA; RNA - genetics; RNA - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M117.808402

It has been long assumed that post-mitotic neurons only utilize the error-prone non-homologous end–joining pathway to repair double-strand breaks (DSBs) associated with oxidative damage to DNA, given the inability of non-replicating neuronal DNA to utilize a sister chromatid template in the less error-prone homologous recombination (HR) repair pathway. However, we and others have found recently that active transcription triggers a replication-independent recombinational repair mechanism in G0/G1 phase of the cell cycle. Here we observed that the HR repair protein RAD52 is recruited to sites of DNA DSBs in terminally differentiated, post-mitotic neurons. This recruitment is dependent on the presence of a nascent mRNA generated during active transcription, providing evidence that an RNA-templated HR repair mechanism exists in non-dividing, terminally differentiated neurons. This recruitment of RAD52 in neurons is decreased by transcription inhibition. Importantly, we found that high concentrations of amyloid β, a toxic protein associated with Alzheimer’s disease, inhibits the expression and DNA damage response of RAD52, potentially leading to a defect in the error-free, RNA-templated HR repair mechanism. This study shows a novel RNA-dependent repair mechanism of DSBs in post-mitotic neurons and demonstrates that defects in this pathway may contribute to neuronal genomic instability and consequent neurodegenerative phenotypes such as those seen in Alzheimer’s disease.