RAD52 Is Required for RNA-templated Recombination Repair in Post-Mitotic Neurons

J Biol Chem. 2018 Jan 26;293(4):1353-1362. doi: 10.1074/jbc.M117.808402. Epub 2017 Dec 7.

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 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.

Keywords: Alzheimer's disease; RNA; amyloid β (Aβ); neuron; oxidative damage; recombination.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • DNA Breaks, Double-Stranded*
  • G1 Phase / physiology
  • Mitosis / physiology*
  • Neurons / cytology
  • Neurons / metabolism*
  • RNA / genetics
  • RNA / metabolism*
  • Rad52 DNA Repair and Recombination Protein / genetics
  • Rad52 DNA Repair and Recombination Protein / metabolism*
  • Rats
  • Recombination, Genetic / physiology*
  • Resting Phase, Cell Cycle / physiology

Substances

  • Rad52 DNA Repair and Recombination Protein
  • RNA