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.

Keywords: PARP inhibition; RMRP; SNRPA1; long noncoding RNA; p53.