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Nuclear poly(A)-binding protein 1 is an ATM target and essential for DNA double-strand break repair

Michal Gavish-Izakson1, Bhagya Bhavana Velpula1, Ran Elkon1

  • 1Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Nucleic Acids Research
|December 19, 2017
PubMed

Insights

Nuclear poly(A)-binding protein 1 (PABPN1) is a novel DNA double-strand break (DSB) repair regulator. ATM phosphorylates PABPN1, crucial for efficient DSB repair via NHEJ and HRR pathways.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Genetics

Background:

  • The DNA damage response (DDR) network is activated by DNA double-strand breaks (DSBs).
  • Ataxia-telangiectasia, mutated (ATM) is a key protein kinase in the DSB response.
  • Nuclear poly(A)-binding protein 1 (PABPN1) typically regulates RNA processing and stability.

Purpose of the Study:

  • To identify novel regulators of the DNA damage response.
  • To investigate the role of nuclear poly(A)-binding protein 1 (PABPN1) in DNA double-strand break (DSB) repair.
  • To elucidate the relationship between ATM kinase and PABPN1 in the DDR.

Main Methods:

  • Cellular localization studies to track PABPN1 during DSB repair.
  • Phosphorylation site analysis of PABPN1.
  • Depletion studies using PABPN1 knockdown or knockout.
  • Assessment of cell-cycle arrest and DSB repair efficiency.
  • Mass spectrometry to identify PABPN1 interacting partners.

Main Results:

  • PABPN1 is recruited to DSB sites and phosphorylated by ATM on Ser95.
  • PABPN1 depletion impairs DSB repair and prolongs G2/M arrest.
  • PABPN1 is essential for both nonhomologous end-joining (NHEJ) and homologous recombination repair (HRR).
  • PABPN1 is critical for DNA-end resection, a key step in HRR.
  • DNA damage induces interactions between phospho-PABPN1 and DDR/RNA-metabolizing proteins.

Conclusions:

  • PABPN1 is a novel ATM target and a critical regulator of DSB repair.
  • PABPN1 integrates RNA metabolism with the DNA damage response.
  • ATM-PABPN1 signaling represents a new axis in DNA repair pathways.

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