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

Starr Welty, Yaqun Teng, Zhuobin Liang, Weixing Zhao, Laurie H Sanders, J Timothy Greenamyre, Maria Eulalia Rubio, Amantha Thathiah, Ravindra Kodali, Ronald Wetzel, Arthur S Levine, Li Lan

The Journal of biological chemistry 2018 Jan 26

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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. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Citation

Starr Welty, Yaqun Teng, Zhuobin Liang, Weixing Zhao, Laurie H Sanders, J Timothy Greenamyre, Maria Eulalia Rubio, Amantha Thathiah, Ravindra Kodali, Ronald Wetzel, Arthur S Levine, Li Lan. RAD52 is required for RNA-templated recombination repair in post-mitotic neurons. The Journal of biological chemistry. 2018 Jan 26;293(4):1353-1362