Combined absence of TRP53 target genes ZMAT3, PUMA and p21 cause a high incidence of cancer in mice

Abstract

Transcriptional activation of target genes is essential for TP53-mediated tumour suppression, though the roles of the diverse TP53-activated target genes in tumour suppression remains poorly understood. Knockdown of ZMAT3, an RNA-binding zinc-finger protein involved in regulating alternative splicing, in haematopoietic cells by shRNA caused leukaemia only with the concomitant absence of the PUMA and p21, the critical effectors of TRP53-mediated apoptosis and cell cycle arrest respectively. We were interested to further investigate the role of ZMAT3 in tumour suppression beyond the haematopoietic system. Therefore, we generated Zmat3 knockout and compound gene knockout mice, lacking Zmat3 and p21, Zmat3 and Puma or all three genes. Puma^-/-p21^-/-Zmat3^-/- triple knockout mice developed tumours at a significantly higher frequency compared to wild-type, Puma^-/-Zmat3^-/- or p21^-/-Zmat3^-/-deficient mice. Interestingly, we observed that the triple knockout and Puma^-/-Zmat3^-/- double deficient animals succumbed to lymphoma, while p21^-/-Zmat3^-/- animals developed mainly solid cancers. This analysis suggests that in addition to ZMAT3 loss, additional TRP53-regulated processes must be disabled simultaneously for TRP53-mediated tumour suppression to fail. Our findings reveal that the absence of different TRP53 regulated tumour suppressive processes changes the tumour spectrum, indicating that different TRP53 tumour suppressive pathways are more critical in different tissues.