NR1D1 Recruitment to Sites of DNA Damage Inhibits Repair and Is Associated with Chemosensitivity of Breast Cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-05, Vol.77 (9), p.2453-2463
• Main Authors: Ka, Na-Lee, Na, Tae-Young, Na, Hyelin, Lee, Min-Ho, Park, Han-Su, Hwang, Sewon, Kim, Il Yong, Seong, Je Kyung, Lee, Mi-Ock
• Format: Article
• Language: English
• Subjects: BRCA1 protein; BRCA1 Protein - genetics; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Cycle Proteins - genetics; Chemotherapy; Clonal deletion; Deoxyribonucleic acid; DNA; DNA Breaks, Double-Stranded - drug effects; DNA damage; DNA Damage - drug effects; DNA End-Joining Repair - drug effects; DNA repair; DNA Repair - drug effects; Doxorubicin; Doxorubicin - administration & dosage; Drug Resistance, Neoplasm - genetics; Female; Gene Expression Regulation, Neoplastic - drug effects; Homologous recombination; Homology; Humans; Lesions; Ligands; MCF-7 Cells; Nuclear Proteins - genetics; Nuclear Receptor Subfamily 1, Group D, Member 1 - genetics; Poly(ADP-ribose) polymerase; Recruitment; Sirtuins - genetics
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-16-2099

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, both and Analysis 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. .