title: NR1D1 Recruitment to Sites of DNA Damage Inhibits Repair and Is Associated with Chemosensitivity of Breast Cancer.
abstract: DNA repair capacity is critical for survival of cancer cells upon therapeutic DNA damage and thus is an important determinant of susceptibility to chemotherapy in cancer patients. In this study, we identified a novel function of nuclear receptor NR1D1 in DNA repair, which enhanced chemosensitivity in breast cancer cells. NR1D1 inhibited both nonhomologous end joining and homologous recombination double-strand breaks repair, and delayed the clearance of γH2AX DNA repair foci that formed after treatment of doxorubicin. PARylation of NR1D1 by PARP1 drove its recruitment to damaged DNA lesions. Deletion of the ligand binding domain of NR1D1 that interacted with PARP1, or treatment of 6-(5H)-phenanthridinone, an inhibitor of PARP1, suppressed the recruitment of NR1D1 to DNA damaged sites, indicating PARylation as a critical step for the NR1D1 recruitment. NR1D1 inhibited recruitment of the components of DNA damage response complex such as SIRT6, pNBS1, and BRCA1 to DNA lesions. Downregulation of NR1D1 in MCF7 cells resulted in resistance to doxorubicin, bothin vitroandin vivoAnalysis of four public patient data sets indicated that NR1D1 expression correlates positively with clinical outcome in breast cancer patients who received chemotherapy. Our findings suggest that NR1D1 and its ligands provide therapeutic options that could enhance the outcomes of chemotherapy in breast cancer patients.Cancer Res; 77(9); 2453-63. ©2017 AACR.
authors.affiliation: College of Pharmacy and Bio-MAX Institute, Seoul National University, Gwanak-gu, Seoul, Korea.
authors.forename: Na-Lee
authors.initials: NL
authors.lastname: Ka
authors.affiliation: College of Pharmacy and Bio-MAX Institute, Seoul National University, Gwanak-gu, Seoul, Korea.
authors.forename: Tae-Young
authors.initials: TY
authors.lastname: Na
authors.affiliation: College of Pharmacy and Bio-MAX Institute, Seoul National University, Gwanak-gu, Seoul, Korea.
authors.forename: Hyelin
authors.initials: H
authors.lastname: Na
authors.affiliation: College of Pharmacy and Bio-MAX Institute, Seoul National University, Gwanak-gu, Seoul, Korea.
authors.forename: Min-Ho
authors.initials: MH
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Bio-MAX Institute, Seoul National University, Gwanak-gu, Seoul, Korea.
authors.forename: Han-Su
authors.initials: HS
authors.lastname: Park
authors.affiliation: College of Pharmacy and Bio-MAX Institute, Seoul National University, Gwanak-gu, Seoul, Korea.
authors.forename: Sewon
authors.initials: S
authors.lastname: Hwang
authors.affiliation: College of Veterinary Medicine, Seoul National University and Korea Mouse Phenotyping Center, Gwanak-gu, Seoul, Korea.
authors.forename: Il Yong
authors.initials: IY
authors.lastname: Kim
authors.affiliation: College of Veterinary Medicine, Seoul National University and Korea Mouse Phenotyping Center, Gwanak-gu, Seoul, Korea.
authors.forename: Je Kyung
authors.initials: JK
authors.lastname: Seong
authors.affiliation: College of Pharmacy and Bio-MAX Institute, Seoul National University, Gwanak-gu, Seoul, Korea. molee@snu.ac.kr.
authors.forename: Mi-Ock
authors.initials: MO
authors.lastname: Lee
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D059766:DNA End-Joining Repair / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects*; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D009687:Nuclear Proteins / Q000235:genetics; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics*; D037761:Sirtuins / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; C112156:NBN protein, human; C064353:NR1D1 protein, human; D009687:Nuclear Proteins; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D004317:Doxorubicin; C516592:SIRT6 protein, human; D037761:Sirtuins