The TP53-activated E3 ligase RNF144B is a tumour suppressor that prevents genomic instability

Abstract The tumor suppressor protein TP53 regulates a vast transcriptional program that serves protective mechanisms against cancer development. However, the complexity of this program makes it difficult to unravel the role of each of its targets in TP53-mediated tumour suppression. ​​Knockdown of RNF144B, a E3-ubiquitin ligase transcriptionally regulated by TP53, enhanced the rate of tumour development and severity of malignant disease in the context of murine c-MYC - driven lymphomagenesis. Here we asked whether RNF144B has an impact on tumor suppression beyond the hematopoietic compartment. Integrative transcriptomics, proteomics, genomics and functional analysis of human and mouse oncogene-expressing cells with TP53 wild-type revealed a role for RNF144B in coordinating cellular proliferation and transformation, DNA repair and genome stability. Moreover, we show that in the context of lung adenocarcinomas, RNF144B deficiency leads to resistance to cytotoxic drugs that induce DNA damage and chromosomal instability, and that patients have a worse disease-survival overall. Supported by clinical data, our study suggests that RNF144B governs genomic stability during transformation suppression, which could explain its inactivation in human cancers.