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

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

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 errorprone 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.

Original languageEnglish (US)
Pages (from-to)1353-1362
Number of pages10
JournalJournal of Biological Chemistry
Volume293
Issue number4
DOIs
StatePublished - Jan 26 2018
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Welty, S., Teng, Y., Liang, Z., Zhao, W., Sanders, L. H., Greenamyre, J. T., Rubio, M. E., Thathiah, A., Kodali, R., Wetzel, R., Levine, A. S., & Lan, L. (2018). RAD52 is required for RNA-templated recombination repair in post-mitotic neurons. Journal of Biological Chemistry, 293(4), 1353-1362. https://doi.org/10.1074/jbc.M117.808402