CtIP suppresses primary microRNA maturation and promotes metastasis of colon cancer cells in a xenograft mouse model
| Autor: | Ya Wang, Shuailin Hao, Hailong Wang, Jianping Ren, Shuyuan Zhang, Yuqin Zhao, Yan Wu, Xingzhi Xu, Lixiu Lin, Youhang Li |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
CtIP C-terminal–binding protein–interacting protein BiFC bimolecular fluorescence complementation EMSA electrophoretic mobility shift assay MRN MRE11–RAD50–NBS1 Biochemistry Metastasis U2OS human osteosarcoma cell line Mice microRNA maturation RAD50 ATP-binding cassette—ATPase Neoplasm Metastasis Rhed RNA-binding heme domain EGFP enhanced GFP biology NBS1 Nijmegen breakage syndrome protein 1 ChIP chromatin immunoprecipitation Cell Transformation Neoplastic Colonic Neoplasms microprocessor DDX5 DEAD-box helicase 5 RNase ribonuclease Research Article PIC protease inhibitor cocktail DGCR8 DNA repair VN Venus N-terminal fragment CtBP C-terminal–binding protein Proto-Oncogene Proteins pp60(c-src) pri-miRNA miRNA primary transcripts DGCR8 DiGeorge syndrome critical region gene 8 Drosha 03 medical and health sciences cDNA complementary DNA MRE11 meiotic recombination 11 RPA replication protein A Cell Line Tumor microRNA GST glutathione-S-transferase medicine metastasis Animals Humans DSB double-strand break Molecular Biology NETN NaCl EDTA Tris–HCl and NP-40 buffer Endodeoxyribonucleases 030102 biochemistry & molecular biology PLA proximity ligation assay Cell Biology medicine.disease VC Venus C-terminal fragment MicroRNAs 030104 developmental biology BRCA1 breast cancer 1 CtIP Tumor progression Rad50 Cancer cell Cancer research biology.protein HR homologous recombination pre-miRNAs precursor miRNAs qPCR quantitative PCR |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | miRNAs are important regulators of eukaryotic gene expression. The post-transcriptional maturation of miRNAs is controlled by the Drosha-DiGeorge syndrome critical region gene 8 (DGCR8) microprocessor. Dysregulation of miRNA biogenesis has been implicated in the pathogenesis of human diseases, including cancers. C-terminal-binding protein-interacting protein (CtIP) is a well-known DNA repair factor that promotes the processing of DNA double-strand break (DSB) to initiate homologous recombination-mediated DSB repair. However, it was unclear whether CtIP has other unknown cellular functions. Here, we aimed to uncover the roles of CtIP in miRNA maturation and cancer cell metastasis. We found that CtIP is a potential regulatory factor that suppresses the processing of miRNA primary transcripts (pri-miRNA). CtIP directly bound to both DGCR8 and pri-miRNAs through a conserved Sae2-like domain, reduced the binding of Drosha to DGCR8 and pri-miRNA substrate, and inhibited processing activity of Drosha complex. CtIP depletion significantly increased the expression levels of a subset of mature miRNAs, including miR-302 family members that are associated with tumor progression and metastasis in several cancer types. We also found that CtIP-inhibited miRNAs, such as miR-302 family members, are not crucial for DSB repair. However, increase of miR-302b levels or loss of CtIP function severely suppressed human colon cancer cell line tumor cell metastasis in a mouse xenograft model. These studies reveal a previously unrecognized mechanism of CtIP in miRNA processing and tumor metastasis that represents a new function of CtIP in cancer. |
| Databáze: | OpenAIRE |
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