H. pylori infection alters repair of DNA double-strand breaks via SNHG17
Taotao Han, … , Jiazeng Sun, Juan Shi
Taotao Han, … , Jiazeng Sun, Juan Shi
Published June 15, 2020
Citation Information: J Clin Invest. 2020;130(7):3901-3918. https://doi.org/10.1172/JCI125581.
View: Text | PDF
Research Article Gastroenterology Oncology Article has an altmetric score of 4

H. pylori infection alters repair of DNA double-strand breaks via SNHG17

Abstract

Chronic infections can lead to carcinogenesis through inflammation-related mechanisms. Chronic infection of the human gastric mucosa with Helicobacter pylori is a well-known risk factor for gastric cancer. However, the mechanisms underlying H. pylori–induced gastric carcinogenesis are incompletely defined. We aimed to screen and clarify the functions of long noncoding RNAs (lncRNAs) that are differentially expressed in H. pylori–related gastric cancer. We found that lncRNA SNHG17 was upregulated by H. pylori infection and markedly increased the levels of double-strand breaks (DSBs). SNHG17 overexpression correlated with poor overall survival in patients with gastric cancer. The recruitment of NONO by overabundant nuclear SNHG17, along with the role of cytoplasmic SNHG17 as a decoy for miR-3909, which regulates Rad51 expression, shifted the DSB repair balance from homologous recombination toward nonhomologous end joining. Notably, during chronic H. pylori infection, SNHG17 knockdown inhibited chromosomal aberrations. Our findings suggest that spatially independent deregulation of the SNHG17/NONO and SNHG17/miR-3909/RING1/Rad51 pathways upon H. pylori infection promotes tumorigenesis in gastric cancer by altering the DNA repair system, which is critical for the maintenance of genomic stability. Upregulation of SNHG17 by H. pylori infection might be an undefined link between cancer and inflammation.

Authors

Taotao Han, Xiaohui Jing, Jiayu Bao, Lianmei Zhao, Aidong Zhang, Renling Miao, Hui Guo, Baoguo Zhou, Shang Zhang, Jiazeng Sun, Juan Shi

×

Figure 8

Nuclear SNHG17 directly interacts with NONO to regulate NHEJ pathway of DSB repair.

Options: View larger image (or click on image) Download as PowerPoint
Nuclear SNHG17 directly interacts with NONO to regulate NHEJ pathway of ...
(A) RNA pull-down analysis of the binding of the purified GST-NONO-RRM1, GST-NONO-RRM2, and GST–full-length NONO (NONO-FL) protein to in vitro–transcribed SNHG17. Samples were assayed more than 3 times. (B) A series of SNHG17 deletion mutants were transcribed in vitro and were used to perform RNA pull-down assays. Samples were assayed more than 3 times. (C) A NONO-binding site was predicated at location 716–720 nt of SNHG17. RNA pull-down analysis of the binding of NONO with SNHG17 probe or mutant SNHG17 probe. Samples were assayed more than 3 times. (D) CRISPR/Cas9 gene-editing–generated mutant SGC-7901 cells were validated by DNA sequencing. (E) NONO RIP followed by qPCR analysis of copurified RNA in CRISPR/Cas9 mutant SGC-7901 cells with or without H. pylori infection. (F) Distribution of primer pairs relative to the DSB created by I-SceI and quantification of NONO relative to the DSB by qRT-PCR. Data are represented as mean ± SEM. n = 3. *P < 0.05; **P < 0.01, 2-tailed Student’s t test (E); ANOVA (F).