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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.

SUBMITTER: Sun Y

PROVIDER: S-EPMC7184567 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Sun Yue Y Ning Xuelian X Fan Jiankun J Hu Jiandong J Jiang Yanting Y Hu Ziqi Z Paulo Joao A JA Liu Jichao J Qiu Xiaohong X Xu Hui H Fu Songbin S Gygi Steven P SP Zhang Jinwei J Zhou Chunshui C

Cell death & disease 20200427 4

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-C ...[more]

PMID: 32341333

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Project description:BackgroundDNA double strand break repair is important to preserve the fidelity of our genetic makeup after DNA damage. Rad50 is one of the components in MRN complex important for DNA repair mechanism. Rad50 mutations can lead to microcephaly, mental retardation and growth retardation in human. However, Rad50 mutations in human and other organisms have never been gathered and heuristically compared for their deleterious effects. It is important to assess the conserved region in Rad50 and its homolog to identify vital mutations that can affect functions of the protein.MethodIn this study, Rad50 mutations were retrieved from SNPeffect 4.0 database and literature. Each of the mutations was analyzed using various bioinformatic analyses such as PredictSNP, MutPred, SNPeffect 4.0, I-Mutant and MuPro to identify its impact on molecular mechanism, biological function and protein stability, respectively.ResultsWe identified 103 mostly occurred mutations in the Rad50 protein domains and motifs, which only 42 mutations were classified as most deleterious. These mutations are mainly situated at the specific motifs such as Walker A, Q-loop, Walker B, D-loop and signature motif of the Rad50 protein. Some of these mutations were predicted to negatively affect several important functional sites that play important roles in DNA repair mechanism and cell cycle signaling pathway, highlighting Rad50 crucial role in this process. Interestingly, mutations located at non-conserved regions were predicted to have neutral/non-damaging effects, in contrast with previous experimental studies that showed deleterious effects. This suggests that software used in this study may have limitations in predicting mutations in non-conserved regions, implying further improvement in their algorithm is needed. In conclusion, this study reveals the priority of acid substitution associated with the genetic disorders. This finding highlights the vital roles of certain residues such as K42E, C681A/S, CC684R/S, S1202R, E1232Q and D1238N/A located in Rad50 conserved regions, which can be considered for a more targeted future studies.

Dataset Information

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

Publications

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

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