Loss of tumor suppressor inositol polyphosphate 4-phosphatase type B impairs DNA double-strand break repair by destabilization of DNA tethering protein Rad50.

Abstract

Genome instability is the fundamental hallmark of malignant tumors. Tumor suppressors often play a role in maintaining genome stability. Our previous genetic screen identified inositol polyphosphate 4-phosphatase type B (INPP4B), primarily hydrolyzing phosphatidylinositol 3, 4-disphosphate, is a potential tumor suppressor in lung cancer cells. How INPP4B regulates the genome stability of lung cancer cells is unclear. Here we report knockout of INPP4B in lung adenocarcinoma A549 cells by Crispr-Cas9 gene editing leads to sensitization to ionizing radiation (IR), PARP inhibitor olaparib and impaired DNA homologous recombination repair. Re-introduction of a Crispr-Cas9 resistant INPP4B gene in the INPP4B knockout cells partially restored their resistance to IR, indicating loss of INPP4B protein is relevant to the increased IR sensitivity. Furthermore, we showed ectopic expressed INPP4B in A549 cells responds to IR irradiation by redistribution from cytoplasm to nucleus and endogenous INPP4B protein interacts with Rad50, a crucial MRN complex component for tethering DNA double-strand breaks. Loss of INPP4B protein results in decreased stability of Rad50 in vivo, suggesting an unanticipated role of tumor suppressor INPP4B in maintaining genome integrity via facilitating Rad50 mediated DNA double-strand break repair. Taken together, our findings support a dual role of INPP4B in suppression of tumorigenesis by safeguarding genome stability, as well as inhibiting of PI3K-Akt-mTOR signaling, and offer a new therapeutic strategy for personalized cancer treatment to patients with INPP4B defects or deficiency in the clinic.

• Authors: Yue Sun, Xuelian Ning, Jiankun Fan, Jiandong Hu, Yanting Jiang, Ziqi Hu, Joao A Paulo, Jichao Liu, Xiaohong Qiu, Hui Xu, Songbin Fu, Steven P Gygi, Jinwei Zhang, Chunshui Zhou
• Journal: Cell death & disease (Cell Death Dis) Vol. 11 Issue 4 Pg. 292 (04 27 2020) ISSN: 2041-4889 [Electronic] England
• PMID: 32341333 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Phosphoric Monoester Hydrolases
• phosphatidylinositol-3,4-bisphosphate 4-phosphatase
• Acid Anhydride Hydrolases
• RAD50 protein, human

Topics

• Acid Anhydride Hydrolases (metabolism)
• Cell Line, Tumor
• DNA Breaks, Double-Stranded (drug effects)
• DNA-Binding Proteins (metabolism)
• Genome (genetics)
• Humans
• Phosphoric Monoester Hydrolases (genetics)
• Signal Transduction