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Detection and Visualization of DNA Damage-induced Protein Complexes in Suspension Cell Cultures Using the Proximity Ligation Assay
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PP2A Regulates Phosphorylation-Dependent Isomerization of Cytoplasmic and Mitochondrial-Associated ATR by Pin1 in DNA

Yetunde Makinwa1, Brian M Cartwright2, Phillip R Musich2

  • 1Department of Cancer Biology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States.

Frontiers in Cell and Developmental Biology
|September 28, 2020
PubMed

Insights

Protein phosphatase 2A (PP2A) regulates the anti-apoptotic function of Ataxia telangiectasia and Rad3-related protein (ATR) at mitochondria. PP2A dephosphorylation of ATR controls its isomerization, impacting cell survival after DNA damage.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • Ataxia telangiectasia and Rad3-related protein (ATR) is a nuclear kinase crucial for DNA damage response.
  • ATR also functions in the cytoplasm as an anti-apoptotic protein at mitochondria, regulated by prolyl isomerase Pin1.
  • Pin1 isomerizes cis ATR to trans ATR at the Ser428-Pro429 motif.

Purpose of the Study:

  • To elucidate the molecular mechanism regulating Pin1-mediated ATR isomerization in the cytoplasm.
  • To identify the phosphatase involved in dephosphorylating ATR at Ser428.
  • To understand how ATR's anti-apoptotic activity at mitochondria is regulated in response to DNA damage.

Main Methods:

  • Investigated the requirement of ATR S428 phosphorylation for Pin1 activity.
  • Identified protein phosphatase 2A (PP2A) as the key phosphatase.
  • Assessed the impact of PP2A inhibition/depletion on cis ATR and trans ATR levels and mitochondrial localization.

Main Results:

  • Pin1-mediated isomerization of cis ATR requires prior phosphorylation of ATR at Ser428.
  • PP2A dephosphorylates ATR Ser428 following DNA damage, increasing anti-apoptotic cis ATR (ATR-H) levels.
  • PP2A inhibition or depletion enhances Pin1 isomerization, reducing cis ATR and increasing trans ATR, affecting mitochondrial localization via tBid binding.

Conclusions:

  • PP2A plays a critical role in regulating ATR's anti-apoptotic function at mitochondria post-DNA damage.
  • The balance between cis and trans ATR forms, modulated by PP2A and Pin1, dictates mitochondrial anti-apoptotic activity.
  • Findings suggest potential therapeutic strategies targeting cis ATR levels in cancer treatment.
Keywords:
ATRATR antiapoptotic activity at mitochondriaBIDDNA damage responsePP2APin1UV irradiation

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