PINX1 loss confers susceptibility to PARP inhibition in pan-cancer cells

• Published in: Cell death & disease Vol. 15; no. 8; pp. 610 - 15
• Main Authors: Huang, Mei, Zhu, Xiaotong, Wang, Chen, He, Liying, Li, Lei, Wang, Haopeng, Fan, Gaofeng, Wang, Yu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.08.2024; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/1; 13/109; 13/44; 14/19; 38/77; 631/337/1427; 631/337/572; 631/67/395; 631/80; 82/29; 82/58; Antibodies; Biochemistry; Biomedical and Life Sciences; BRCA1 protein; Breast cancer; Cancer; Cancer therapies; Cell Biology; Cell Culture; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Chromatin remodeling; DNA Damage; DNA repair; DNA Repair - drug effects; Etoposide; Etoposide - pharmacology; Gene regulation; Genotoxicity; Humans; Immunology; Lethality; Life Sciences; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors; Poly (ADP-Ribose) Polymerase-1 - genetics; Poly (ADP-Ribose) Polymerase-1 - metabolism; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Telomerase; Telomerase inhibitors; Transcription; Tumor cell lines; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; X-ray Repair Cross Complementing Protein 1; XRCC1 protein
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-024-07009-6

PARP1 is crucial in DNA damage repair, chromatin remodeling, and transcriptional regulation. The principle of synthetic lethality has effectively guided the application of PARP inhibitors in treating tumors carrying BRCA1/2 mutations. Meanwhile, PARP inhibitors have exhibited efficacy in BRCA-proficient patients, further highlighting the necessity for a deeper understanding of PARP1 function and its inhibition in cancer therapy. Here, we unveil PIN2/TRF1-interacting telomerase inhibitor 1 (PINX1) as an uncharacterized PARP1-interacting protein that synergizes with PARP inhibitors upon its depletion across various cancer cell lines. Loss of PINX1 compromises DNA damage repair capacity upon etoposide treatment. The vulnerability of PINX1-deficient cells to etoposide and PARP inhibitors could be effectively restored by introducing either a full-length or a mutant form of PINX1 lacking telomerase inhibitory activity. Mechanistically, PINX1 is recruited to DNA lesions through binding to the ZnF3-BRCT domain of PARP1, facilitating the downstream recruitment of the DNA repair factor XRCC1. In the absence of DNA damage, PINX1 constitutively binds to PARP1, promoting PARP1-chromatin association and transcription of specific DNA damage repair proteins, including XRCC1, and transcriptional regulators, including GLIS3. Collectively, our findings identify PINX1 as a multifaceted partner of PARP1, crucial for safeguarding cells against genotoxic stress and emerging as a potential candidate for targeted tumor therapy.