title: PTIP associates with Artemis to dictate DNA repair pathway choice.
abstract: PARP inhibitors (PARPis) are being used in patients with BRCA1/2 mutations. However, doubly deficient BRCA1(-/-)53BP1(-/-) cells or tumors become resistant to PARPis. Since 53BP1 or its known downstream effectors, PTIP and RIF1 (RAP1-interacting factor 1 homolog), lack enzymatic activities directly implicated in DNA repair, we decided to further explore the 53BP1-dependent pathway. In this study, we uncovered a nuclease, Artemis, as a PTIP-binding protein. Loss of Artemis restores PARPi resistance in BRCA1-deficient cells. Collectively, our data demonstrate that Artemis is the major downstream effector of the 53BP1 pathway, which prevents end resection and promotes nonhomologous end-joining and therefore directly competes with the homologous recombination repair pathway.
authors.affiliation: Institute of Systems Biomedicine, Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China; Department of Experimental Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
authors.forename: Jiadong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Radiation Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390;
authors.forename: Asaithamby
authors.initials: A
authors.lastname: Aroumougame
authors.affiliation: Radiation Biology and DNA Repair Laboratory, Darmstadt University of Technology, 64287 Darmstadt, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Lobrich
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
authors.forename: Yujing
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Radiation Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390;
authors.forename: David
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; jchen8@mdanderson.org zgong@mdanderson.org.
authors.forename: Junjie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; jchen8@mdanderson.org zgong@mdanderson.org.
authors.forename: Zihua
authors.initials: Z
authors.lastname: Gong
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins; D004720:Endonucleases; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C485876:PAXIP1 protein, human; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; C426344:DCLRE1C protein, human; D004720:Endonucleases
keywords: 53BP1; Artemis; BRCA1; DNA repair; PARP inhibition; PTIP