title: ATR Plays a Direct Antiapoptotic Role at Mitochondria, which Is Regulated by Prolyl Isomerase Pin1.
abstract: 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.
authors.affiliation: Department of Biomedical Sciences, J.H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Hilton
authors.affiliation: Department of Biomedical Sciences, J.H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
authors.forename: Zhengke
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Biomedical Sciences, J.H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
authors.forename: Phillip R
authors.initials: PR
authors.lastname: Musich
authors.affiliation: Department of Biomedical Sciences, J.H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Biomedical Sciences, J.H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Cartwright
authors.affiliation: Department of Biomedical Sciences, J.H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
authors.forename: Moises
authors.initials: M
authors.lastname: Serrano
authors.affiliation: Department of Medicine, Center for Life Science, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Xiao Zhen
authors.initials: XZ
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Center for Life Science, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Kun Ping
authors.initials: KP
authors.lastname: Lu
authors.affiliation: Department of Biomedical Sciences, J.H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. Electronic address: zouy@etsu.edu.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zou
mesh_terms: D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000737:chemistry / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D001665:Binding Sites; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage; D005786:Gene Expression Regulation; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000528:radiation effects*; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D011487:Protein Conformation; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494826:BAX protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase