The RNF20/40 complex regulates p53-dependent gene transcription and mRNA splicing

Chen Wu; Yaqi Cui; Xiuhua Liu; Feng Zhang; Lin-Yu Lu; Xiaochun Yu

doi:10.1093/jmcb/mjz045

The RNF20/40 complex regulates p53-dependent gene transcription and mRNA splicing

J Mol Cell Biol. 2020 Feb 20;12(2):113-124. doi: 10.1093/jmcb/mjz045.

Authors

Chen Wu^{1

2}, Yaqi Cui^{1

2}, Xiuhua Liu¹, Feng Zhang³, Lin-Yu Lu^{4

5}, Xiaochun Yu²

Affiliations

¹ College of Life Sciences, Hebei University, Baoding 071000, China.
² Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
³ College of Life and Environment Sciences, Shanghai Normal University, Shanghai, China.
⁴ Key Laboratory of Reproductive Genetics, Ministry of Education and Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
⁵ Institute of Translational Medicine, Zhejiang University, Hangzhou, China.

Abstract

p53 is a key transcription factor to regulate gene transcription. However, the molecular mechanism of chromatin-associated p53 on gene transcription remains elusive. Here, using unbiased protein affinity purification, we found that the RNF20/40 complex associated with p53 on the chromatin. Further analyses indicated that p53 mediated the recruitment of the RNF20/40 complex to p53 target gene loci including p21 and PUMA loci and regulated the transcription of p21 and PUMA via the RNF20/40 complex-dependent histone H2B ubiquitination (ubH2B). Lacking the RNF20/40 complex suppressed not only ubH2B but also the generation of the mature mRNA of p21 and PUMA. Moreover, ubH2B was recognized by the ubiquitin-binding motif of pre-mRNA processing splicing factor 8 (PRPF8), a subunit in the spliceosome, and PRPF8 was required for the maturation of the mRNA of p21 and PUMA. Our study unveils a novel p53-dependent pathway that regulates mRNA splicing for tumor suppression.

Keywords: PUMA; p21; RNF20; RNF40; gene transcription; p53.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Gene Expression Regulation, Neoplastic
HCT116 Cells
Humans
K562 Cells
Protein Interaction Domains and Motifs
RNA Interference
RNA Splicing / genetics*
RNA, Messenger / metabolism*
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism
Transcription, Genetic / genetics*
Tumor Suppressor Protein p53 / chemistry
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism*
Ubiquitin-Protein Ligases / chemistry
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*
Ubiquitination / genetics

Substances

PRPF8 protein, human
RNA, Messenger
RNA-Binding Proteins
TP53 protein, human
Tumor Suppressor Protein p53
RNF20 protein, human
RNF40 protein, human
Ubiquitin-Protein Ligases