Inactivation of the tumor suppressor p53 by long noncoding RNA RMRP.

Abstract

p53 inactivation is highly associated with tumorigenesis and drug resistance. Here, we identify a long noncoding RNA, the RNA component of mitochondrial RNA-processing endoribonuclease (RMRP), as an inhibitor of p53. RMRP is overexpressed and associated with an unfavorable prognosis in colorectal cancer. Ectopic RMRP suppresses p53 activity by promoting MDM2-induced p53 ubiquitination and degradation, while depletion of RMRP activates the p53 pathway. RMRP also promotes colorectal cancer growth and proliferation in a p53-dependent fashion in vitro and in vivo. This anti-p53 action of RMRP is executed through an identified partner protein, SNRPA1. RMRP can interact with SNRPA1 and sequester it in the nucleus, consequently blocking its lysosomal proteolysis via chaperone-mediated autophagy. The nuclear SNRPA1 then interacts with p53 and enhances MDM2-induced proteasomal degradation of p53. Remarkably, ablation of SNRPA1 completely abrogates RMRP regulation of p53 and tumor cell growth, indicating that SNRPA1 is indispensable for the anti-p53 function of RMRP. Interestingly and significantly, poly (ADP-ribose) polymerase (PARP) inhibitors induce RMRP expression through the transcription factor C/EBPβ, and RMRP confers tumor resistance to PARP inhibition by preventing p53 activation. Altogether, our study demonstrates that RMRP plays an oncogenic role by inactivating p53 via SNRPA1 in colorectal cancer.

• Authors: Yajie Chen, Qian Hao, Shanshan Wang, Mingming Cao, Yingdan Huang, Xiaoling Weng, Jieqiong Wang, Zhen Zhang, Xianghuo He, Hua Lu, Xiang Zhou
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 118 Issue 29 (07 20 2021) ISSN: 1091-6490 [Electronic] United States
• PMID: 34266953 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 the Author(s). Published by PNAS.

Chemical References

• RMRP non-coding RNA, human
• RNA, Long Noncoding
• Ribonucleoprotein, U2 Small Nuclear
• TP53 protein, human
• Tumor Suppressor Protein p53
• U2A' protein, human
• Proto-Oncogene Proteins c-mdm2

Topics

• Cell Line, Tumor
• Cell Proliferation
• Colorectal Neoplasms (genetics, metabolism)
• Down-Regulation
• Gene Expression Regulation, Neoplastic
• Humans
• Protein Binding
• Proto-Oncogene Proteins c-mdm2 (genetics, metabolism)
• RNA, Long Noncoding (genetics, metabolism)
• Ribonucleoprotein, U2 Small Nuclear (genetics, metabolism)
• Tumor Suppressor Protein p53 (genetics, metabolism)