ZHX3 is involved in senescent phenotypes.

(A) Schematic diagram of the Zhx3 gene locus in wild type (WT) and Zhx3-knockout (KO) alleles. Arrows indicate primers used for genotyping PCR. (B) Genotyping PCR of WT, heterozygous and homozygous Zhx3-KO mice. (C) RT-qPCR analysis of p16^INK4a in tissues of 7-week-old WT and KO mice. Values shown are mean +/- standard deviation (each n = 3), using the Student’s t-test (*p<0.05, **p<0.01). (D) Kaplan-Meier survival curves of male WT and Zhx3-KO mice (each n = 9). (E) Proposed model of the role of ZHX3 in preventing cellular senescence. ZHX3 and its cofactors (ACLY and RNA metabolism proteins) suppress p16^INK4a and ribosomal RNA gene transcription, which promotes mitochondrial–nucleolar activation in senescent cells.