ATR Plays a Direct Antiapoptotic Role at Mitochondria, which Is Regulated by Prolyl Isomerase Pin1

Mol Cell. 2015 Oct 1;60(1):35-46. doi: 10.1016/j.molcel.2015.08.008. Epub 2015 Sep 18.


ATR, a PI3K-like protein kinase, plays a key role in regulating DNA damage responses. Its nuclear checkpoint kinase function is well documented, but little is known about its function outside the nucleus. Here we report that ATR has an antiapoptotic activity at mitochondria in response to UV damage, and this activity is independent of its hallmark checkpoint/kinase activity and partner ATRIP. ATR contains a BH3-like domain that allows ATR-tBid interaction at mitochondria, suppressing cytochrome c release and apoptosis. This mitochondrial activity of ATR is downregulated by Pin1 that isomerizes ATR from cis-isomer to trans-isomer at the phosphorylated Ser428-Pro429 motif. However, UV inactivates Pin1 via DAPK1, stabilizing the pro-survival cis-isomeric ATR. In contrast, nuclear ATR remains in the trans-isoform disregarding UV. This cytoplasmic response of ATR may provide a mechanism for the observed antiapoptotic role of ATR in suppressing carcinogenesis and its inhibition in sensitizing anticancer agents for killing of cancer cells.

Publication types

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

MeSH terms

  • Apoptosis
  • Ataxia Telangiectasia Mutated Proteins / chemistry
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • BH3 Interacting Domain Death Agonist Protein / metabolism*
  • Binding Sites
  • Cell Line, Tumor
  • Cytochromes c / metabolism
  • DNA Damage
  • Gene Expression Regulation
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • Mitochondria / genetics
  • Mitochondria / radiation effects*
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Peptidylprolyl Isomerase / metabolism*
  • Protein Conformation
  • bcl-2-Associated X Protein / metabolism


  • BAX protein, human
  • BH3 Interacting Domain Death Agonist Protein
  • BID protein, human
  • NIMA-Interacting Peptidylprolyl Isomerase
  • bcl-2-Associated X Protein
  • Cytochromes c
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • PIN1 protein, human
  • Peptidylprolyl Isomerase